Publications by authors named "Liisa K Selin"

58 Publications

T cells in the brain enhance neonatal mortality during peripheral LCMV infection.

PLoS Pathog 2021 01 5;17(1):e1009066. Epub 2021 Jan 5.

University of Massachusetts Medical School, Department of Pathology, Worcester, Massachusetts, United States of America.

In adult mice the severity of disease from viral infections is determined by the balance between the efficiency of the immune response and the magnitude of viral load. Here, the impact of this dynamic is examined in neonates. Newborns are highly susceptible to infections due to poor innate responses, lower numbers of T cells and Th2-prone immune responses. Eighty-percent of 7-day old mice, immunologically equivalent to human neonates, succumbed to extremely low doses (5 PFU) of the essentially non-lethal lymphocytic choriomeningitis virus (LCMV-Armstrong) given intraperitoneally. This increased lethality was determined to be dependent upon poor early viral control, as well as, T cells and perforin as assessed in knockout mice. By day 3, these neonatal mice had 400-fold higher viral loads as compared to adults receiving a 10,000-fold (5X104 PFU) higher dose of LCMV. The high viral load in combination with the subsequent immunological defect of partial CD8 T cell clonal exhaustion in the periphery led to viral entry and replication in the brain. Within the brain, CD8 T cells were protected from exhaustion, and thus were able to mediate lethal immunopathology. To further delineate the role of early viral control, neonatal mice were infected with Pichinde virus, a less virulent arenavirus, or LCMV was given to pups of LCMV-immune mothers. In both cases, peak viral load was at least 29-fold lower, leading to functional CD8 T cell responses and 100% survival.
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http://dx.doi.org/10.1371/journal.ppat.1009066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785120PMC
January 2021

Epstein-Barr Virus Epitope-Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires.

mBio 2020 03 17;11(2). Epub 2020 Mar 17.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "" clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1 and BMLF1, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRα CDR3 motifs played a dominant role, while TCRβ played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. Several lines of evidence suggest that TCRα and TCRβ repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, α and β. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCRα and TCRβ repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection.
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http://dx.doi.org/10.1128/mBio.00250-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078470PMC
March 2020

CDR3α drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection.

PLoS Pathog 2019 11 25;15(11):e1008122. Epub 2019 Nov 25.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRαβ sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCRα chain. For the first time, we identify a CDR3α (complementarity determining region 3 α) motif, KDTDKL, resulting from an obligate AV8.1-AJ34 pairing that was shared by all four individuals studied. This observation coupled with the fact that this public AV8.1-KDTDKL-AJ34 TCR pairs with multiple different TCRβ chains within the same donor (median 4; range: 1-9), suggests that there are some unique structural features of the interaction between the YVL-BR/MHC and the AV8.1-KDTDKL-AJ34 TCR that leads to this high level of selection. Newly developed TCR motif algorithms identified a lysine at position 1 of the CDR3α motif that is highly conserved and likely important for antigen recognition. Crystal structure analysis of the YVL-BR/HLA-A2 complex revealed that the MHC-bound peptide bulges at position 4, exposing a negatively charged aspartic acid that may interact with the positively charged lysine of CDR3α. TCR cloning and site-directed mutagenesis of the CDR3α lysine ablated YVL-BR-tetramer staining and substantially reduced CD69 upregulation on TCR mutant-transduced cells following antigen-specific stimulation. Reduced activation of T cells expressing this CDR3 motif was also observed following exposure to mutated (D4A) peptide. In summary, we show that a highly public TCR repertoire to an immunodominant epitope of a common human virus is almost completely selected on the basis of CDR3α and provide a likely structural basis for the selection. These studies emphasize the importance of examining TCRα, as well as TCRβ, in understanding the CD8 T cell receptor repertoire.
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http://dx.doi.org/10.1371/journal.ppat.1008122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901265PMC
November 2019

Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires.

mBio 2017 Dec 5;8(6). Epub 2017 Dec 5.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M1 (IAV-M1) and EBV BMLF1 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter. The pathogenic impact of immune responses that by chance cross-react to unrelated viruses has not been established in human infections. Here, we demonstrate that the severity of acute infectious mononucleosis (AIM), an Epstein-Barr virus (EBV)-induced disease prevalent in young adults but not children, is associated with increased frequencies of T cells cross-reactive to EBV and the commonly acquired influenza A virus (IAV). The T-cell receptor (TCR) repertoire and functions of these cross-reactive T cells differed between mild- and severe-AIM patients, most likely because these two groups of patients had selected different memory TCR repertoires in response to IAV infections encountered earlier. This heterologous immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools. This study provides a new framework for understanding the role of heterologous immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology.
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http://dx.doi.org/10.1128/mBio.01841-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717389PMC
December 2017

Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy.

Front Immunol 2017 4;8:1210. Epub 2017 Oct 4.

Núcleo de Bioinformática do Laboratório de Imunogenética (NBLI), Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Immunotherapy has become one of the most promising avenues for cancer treatment, making use of the patient's own immune system to eliminate cancer cells. Clinical trials with T-cell-based immunotherapies have shown dramatic tumor regressions, being effective in multiple cancer types and for many different patients. Unfortunately, this progress was tempered by reports of serious (even fatal) side effects. Such therapies rely on the use of cytotoxic T-cell lymphocytes, an essential part of the adaptive immune system. Cytotoxic T-cells are regularly involved in surveillance and are capable of both eliminating diseased cells and generating protective immunological memory. The specificity of a given T-cell is determined through the structural interaction between the T-cell receptor (TCR) and a peptide-loaded major histocompatibility complex (MHC); i.e., an intracellular peptide-ligand displayed at the cell surface by an MHC molecule. However, a given TCR can recognize different peptide-MHC (pMHC) complexes, which can sometimes trigger an unwanted response that is referred to as T-cell cross-reactivity. This has become a major safety issue in TCR-based immunotherapies, following reports of melanoma-specific T-cells causing cytotoxic damage to healthy tissues (e.g., heart and nervous system). T-cell cross-reactivity has been extensively studied in the context of viral immunology and tissue transplantation. Growing evidence suggests that it is largely driven by structural similarities of seemingly unrelated pMHC complexes. Here, we review recent reports about the existence of pMHC "hot-spots" for cross-reactivity and propose the existence of a TCR interaction profile (i.e., a refinement of a more general TCR footprint in which some amino acid residues are more important than others in triggering T-cell cross-reactivity). We also make use of available structural data and pMHC models to interpret previously reported cross-reactivity patterns among virus-derived peptides. Our study provides further evidence that structural analyses of pMHC complexes can be used to assess the intrinsic likelihood of cross-reactivity among peptide-targets. Furthermore, we hypothesize that some apparent inconsistencies in reported cross-reactivities, such as a preferential directionality, might also be driven by particular structural features of the targeted pMHC complex. Finally, we explain why TCR-based immunotherapy provides a special context in which meaningful T-cell cross-reactivity predictions can be made.
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http://dx.doi.org/10.3389/fimmu.2017.01210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632759PMC
October 2017

Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory.

PLoS Pathog 2017 Aug 21;13(8):e1006544. Epub 2017 Aug 21.

Dept of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation. The dysregulation of CD8+ T cell responses in the absence of ZBTB32 was catastrophic, as Zbtb32-/- mice succumbed to a systemic viral infection and showed evidence of severe lung pathology. We found that ZBTB32 and Blimp-1 were co-expressed following CD8+ T cell activation, bound to each other, and cooperatively regulated Blimp-1 target genes Eomes and Cd27. These findings demonstrate that ZBTB32 is a key transcription factor in CD8+ effector T cells that is required for the balanced regulation of effector versus memory responses to infection.
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http://dx.doi.org/10.1371/journal.ppat.1006544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578684PMC
August 2017

Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion.

J Allergy Clin Immunol 2017 10 16;140(4):1206-1210. Epub 2017 Jun 16.

Department of Pathology, University of Massachusetts Medical School, Worcester, Mass; Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669360PMC
October 2017

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8 T cell epitope.

Nat Struct Mol Biol 2017 04 27;24(4):395-406. Epub 2017 Feb 27.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

A keystone of antiviral immunity is CD8 T cell recognition of viral peptides bound to MHC-I proteins. The recognition modes of individual T cell receptors (TCRs) have been studied in some detail, but the role of TCR variation in providing a robust response to viral antigens is unclear. The influenza M1 epitope is an immunodominant target of CD8 T cells that help to control influenza in HLA-A2 individuals. Here we show that CD8 T cells use many distinct TCRs to recognize HLA-A2-M1, which enables the use of different structural solutions to the problem of specifically recognizing a relatively featureless peptide antigen. The vast majority of responding TCRs target a small cleft between HLA-A2 and the bound M1 peptide. These broad repertoires lead to plasticity in antigen recognition and protection against T cell clonal loss and viral escape.
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http://dx.doi.org/10.1038/nsmb.3383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383516PMC
April 2017

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection.

J Virol 2017 Jan 3;91(2). Epub 2017 Jan 3.

Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

One's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of heterologous immunity. This can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study heterologous immunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMV+MCMV), they had more severe immunopathology, enhanced viral burden in multiple organs, and suppression of MCMV-specific T cell memory inflation. MCMV infection initially reduced the numbers of LCMV-specific memory T cells, but continued MCMV persistence did not further erode memory T cells specific to LCMV. When MCMV infection was given first (MCMV+LCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly defined putative MCMV epitope sequence, M57, and the normally subdominant LCMV epitope L, indicating a profound private specificity effect in heterologous immunity between these two viruses. These results further illustrate how a history of an acute or a persistent virus infection can substantially influence the immune responses and immune pathology associated with acute or persistent infections with an unrelated virus.

Importance: This study extends our understanding of heterologous immunity in the context of persistent viral infection. The phenomenon has been studied mostly with viruses such as LCMV that are cleared, but the situation can be more complex with a persistent virus such as MCMV. We found that the history of LCMV infection intensifies MCMV immunopathology, enhances MCMV burden in multiple organs, and suppresses MCMV-specific T cell memory inflation. In the reverse infection sequence, we show that some of the long-term MCMV-immune mice mount a robust CD8 T cell cross-reactive response between a newly defined putative MCMV epitope sequence and a normally subdominant LCMV epitope. These results further illustrate how a history of infection can substantially influence the immune responses and immune pathology associated with infections with an unrelated virus.
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http://dx.doi.org/10.1128/JVI.01386-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215326PMC
January 2017

Editorial overview: Viral immunology.

Curr Opin Virol 2016 Feb 12;16:vii-ix. Epub 2016 Mar 12.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address:

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http://dx.doi.org/10.1016/j.coviro.2016.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128988PMC
February 2016

Increased Immune Response Variability during Simultaneous Viral Coinfection Leads to Unpredictability in CD8 T Cell Immunity and Pathogenesis.

J Virol 2015 Nov 12;89(21):10786-801. Epub 2015 Aug 12.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Unlabelled: T cell memory is usually studied in the context of infection with a single pathogen in naive mice, but how memory develops during a coinfection with two pathogens, as frequently occurs in nature or after vaccination, is far less studied. Here, we questioned how the competition between immune responses to two viruses in the same naive host would influence the development of CD8 T cell memory and subsequent disease outcome upon challenge. Using two different models of coinfection, including the well-studied lymphocytic choriomeningitis (LCMV) and Pichinde (PICV) viruses, several differences were observed within the CD8 T cell responses to either virus. Compared to single-virus infection, coinfection resulted in substantial variation among mice in the size of epitope-specific T cell responses to each virus. Some mice had an overall reduced number of virus-specific cells to either one of the viruses, and other mice developed an immunodominant response to a normally subdominant, cross-reactive epitope (nucleoprotein residues 205 to 212, or NP205). These changes led to decreased protective immunity and enhanced pathology in some mice upon challenge with either of the original coinfecting viruses. In mice with PICV-dominant responses, during a high-dose challenge with LCMV clone 13, increased immunopathology was associated with a reduced number of LCMV-specific effector memory CD8 T cells. In mice with dominant cross-reactive memory responses, during challenge with PICV increased immunopathology was directly associated with these cross-reactive NP205-specific CD8 memory cells. In conclusion, the inherent competition between two simultaneous immune responses results in significant alterations in T cell immunity and subsequent disease outcome upon reexposure.

Importance: Combination vaccines and simultaneous administration of vaccines are necessary to accommodate required immunizations and maintain vaccination rates. Antibody responses generally correlate with protection and vaccine efficacy. However, live attenuated vaccines also induce strong CD8 T cell responses, and the impact of these cells on subsequent immunity, whether beneficial or detrimental, has seldom been studied, in part due to the lack of known T cell epitopes to vaccine viruses. We questioned if the inherent increased competition and stochasticity between two immune responses during a simultaneous coinfection would significantly alter CD8 T cell memory in a mouse model where CD8 T cell epitopes are clearly defined. We show that some of the coinfected mice have sufficiently altered memory T cell responses that they have decreased protection and enhanced immunopathology when reexposed to one of the two viruses. These data suggest that a better understanding of human T cell responses to vaccines is needed to optimize immunization strategies.
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http://dx.doi.org/10.1128/JVI.01432-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621125PMC
November 2015

Evaluation of non-reciprocal heterologous immunity between unrelated viruses.

Virology 2015 Aug 31;482:89-97. Epub 2015 Mar 31.

Department of Pathology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605-2324, USA.

Heterologous immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of immunity to a second unrelated pathogen. Previous investigations have shown that heterologous immunity is not necessarily reciprocal, such as in the case of vaccinia virus (VACV). Replication of VACV is reduced in mice immune to a variety of pathogens, while VACV fails to induce immunity to several of the same pathogens, including lymphocytic choriomeningitis virus (LCMV). Here we examine the lack of reciprocity of heterologous immunity between VACV and LCMV and find that they induce qualitatively different memory CD8 T cells. However, depending on the repertoire of an individual host, VACV can provide protection against LCMV simply by experimentally amplifying the quantity of T cells cross-reactive with the two viruses. Thus, one cause for lack of reciprocity is differences in the frequencies of cross-reactive T cells in immune hosts.
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http://dx.doi.org/10.1016/j.virol.2015.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461541PMC
August 2015

Narrowing of human influenza A virus-specific T cell receptor α and β repertoires with increasing age.

J Virol 2015 Apr 21;89(8):4102-16. Epub 2015 Jan 21.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Unlabelled: Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV Vα and Vβ T cell repertoires specific to M1 residues 58 to 66 (M158-66), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The Vα repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diversity but a preferential retention of T cell repertoires with features of enhanced cross-reactivity.

Importance: With increasing age, the immune system undergoes drastic changes, and older individuals have declined resistance to infections. Vaccinations become less effective, and infection with influenza A virus in older individuals is associated with higher morbidity and mortality. Here, we questioned whether T cell responses directed against the highly conserved HLA-A2-restricted M158-66 peptide of IAV evolves with increasing age. Specifically, we postulated that CD8 T cell repertoires narrow with recurrent exposure and may thus be less efficient in response to new infections with new strains of IAV. Detailed analyses of the VA and VB TCR repertoires simultaneously showed a direct correlation between increasing age and narrowing of the TCR repertoire. Features of the TCRs indicated potentially enhanced cross-reactivity in all older donors. In summary, T cell repertoire analysis in older individuals may be useful as one of the predictors of protection after vaccination.
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http://dx.doi.org/10.1128/JVI.03020-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442365PMC
April 2015

Vaccination and heterologous immunity: educating the immune system.

Trans R Soc Trop Med Hyg 2015 Jan;109(1):62-9

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA

This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) heterologous immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and heterologous immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols?
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http://dx.doi.org/10.1093/trstmh/tru198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351360PMC
January 2015

Regulatory T cells resist virus infection-induced apoptosis.

J Virol 2015 Feb 3;89(4):2112-20. Epub 2014 Dec 3.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Unlabelled: Regulatory T (Treg) cells are important in the maintenance of self-tolerance, and the depletion of Treg cells correlates with autoimmune development. It has been shown that type I interferon (IFN) responses induced early in the infection of mice can drive memory (CD44hi) CD8 and CD4 T cells into apoptosis, and we questioned here whether the apoptosis of CD44-expressing Treg cells might be involved in the infection-associated autoimmune development. Instead, we found that Treg cells were much more resistant to apoptosis than CD44hi CD8 and CD4 T cells at days 2 to 3 after lymphocytic choriomeningitis virus infection, when type I IFN levels are high. The infection caused a downregulation of the interleukin-7 (IL-7) receptor, needed for survival of conventional T cells, while increasing on Treg cells the expression of the high-affinity IL-2 receptor, needed for STAT5-dependent survival of Treg cells. The stably maintained Treg cells early during infection may explain the relatively low incidence of autoimmune manifestations among infected patients.

Importance: Autoimmune diseases are controlled in part by regulatory T cells (Treg) and are thought to sometimes be initiated by viral infections. We tested the hypothesis that Treg may die off at early stages of infection, when virus-induced factors kill other lymphocyte types. Instead, we found that Treg resisted this cell death, perhaps reducing the tendency of viral infections to cause immune dysfunction and induce autoimmunity.
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http://dx.doi.org/10.1128/JVI.02245-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338871PMC
February 2015

Innate PLZF+CD4+ αβ T cells develop and expand in the absence of Itk.

J Immunol 2014 Jul 13;193(2):673-87. Epub 2014 Jun 13.

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and

T cell development in the thymus produces multiple lineages of cells, including innate T cells. Studies in mice harboring alterations in TCR signaling proteins or transcriptional regulators have revealed an expanded population of CD4(+) innate T cells in the thymus that produce IL-4 and express the transcription factor promyelocytic leukemia zinc finger (PLZF). In these mice, IL-4 produced by the CD4(+)PLZF(+) T cell population leads to the conversion of conventional CD8(+) thymocytes into innate CD8(+) T cells resembling memory T cells expressing eomesodermin. The expression of PLZF, the signature invariant NKT cell transcription factor, in these innate CD4(+) T cells suggests that they might be a subset of αβ or γδ TCR(+) NKT cells or mucosal-associated invariant T (MAIT) cells. To address these possibilities, we characterized the CD4(+)PLZF(+) innate T cells in itk(-/-) mice. We show that itk(-/-) innate PLZF(+)CD4(+) T cells are not CD1d-dependent NKT cells, MR1-dependent MAIT cells, or γδ T cells. Furthermore, although the itk(-/-) innate PLZF(+)CD4(+) T cells express αβ TCRs, neither β2-microglobulin-dependent MHC class I nor any MHC class II molecules are required for their development. In contrast to invariant NKT cells and MAIT cells, this population has a highly diverse TCRα-chain repertoire. Analysis of peripheral tissues indicates that itk(-/-) innate PLZF(+)CD4(+) T cells preferentially home to spleen and mesenteric lymph nodes owing to increased expression of gut-homing receptors, and that their expansion is regulated by commensal gut flora. These data support the conclusion that itk(-/-) innate PLZF(+)CD4(+) T cells are a novel subset of innate T cells.
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http://dx.doi.org/10.4049/jimmunol.1302058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083617PMC
July 2014

Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response.

Front Immunol 2013 20;4:475. Epub 2013 Dec 20.

Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.

The balance between protective immunity and immunopathology often determines the fate of the virus-infected host. How rapidly virus is cleared is a function of initial viral load, viral replication rate, and efficiency of the immune response. Here, we demonstrate, with three different inocula of lymphocytic choriomeningitis virus (LCMV), how the race between virus replication and T cell responses can result in different disease outcomes. A low dose of LCMV generated efficient CD8 T effector cells, which cleared the virus with minimal lung and liver pathology. A high dose of LCMV resulted in clonal exhaustion of T cell responses, viral persistence, and little immunopathology. An intermediate dose only partially exhausted the T cell responses and resulted in significant mortality, and the surviving mice developed viral persistence and massive immunopathology, including necrosis of the lungs and liver. This suggests that for non-cytopathic viruses like LCMV, hepatitis C virus, and hepatitis B virus, clonal exhaustion may be a protective mechanism preventing severe immunopathology and death.
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http://dx.doi.org/10.3389/fimmu.2013.00475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869045PMC
January 2014

PC61 (anti-CD25) treatment inhibits influenza A virus-expanded regulatory T cells and severe lung pathology during a subsequent heterologous lymphocytic choriomeningitis virus infection.

J Virol 2013 Dec 18;87(23):12636-47. Epub 2013 Sep 18.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 H1N1 pandemic. This pathology is induced by IAV-specific memory CD8(+) T cells cross-reactive with LCMV. Here, we discovered that IAV-immune mice have enhanced CD4(+) Foxp3(+) T-regulatory (Treg) cells in their lungs, leading us to question whether a modulation in the normal balance of Treg and effector T-cell responses also contributes to enhancing lung pathology upon LCMV infection of IAV-immune mice. Treg cell and interleukin-10 (IL-10) levels remained elevated in the lungs and mediastinal lymph nodes (mLNs) throughout the acute LCMV response of IAV-immune mice. PC61 treatment, used to decrease Treg cell levels, did not change LCMV titers but resulted in a surprising decrease in lung pathology upon LCMV infection in IAV-immune but not in naive mice. Associated with this decrease in pathology was a retention of Treg in the mLN and an unexpected partial clonal exhaustion of LCMV-specific CD8(+) T-cell responses only in IAV-immune mice. PC61 treatment did not affect cross-reactive memory CD8(+) T-cell proliferation. These results suggest that in the absence of IAV-expanded Treg cells and in the presence of cross-reactive memory, the LCMV-specific response was overstimulated and became partially exhausted, resulting in a decreased effector response. These studies suggest that Treg cells generated during past infections can influence the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. Thus, in humans with complex infection histories, PC61 treatment may lead to unexpected results.
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http://dx.doi.org/10.1128/JVI.00936-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838166PMC
December 2013

A small jab - a big effect: nonspecific immunomodulation by vaccines.

Trends Immunol 2013 Sep 14;34(9):431-9. Epub 2013 May 14.

Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Institute of Clinical Research, University of Southern Denmark, and Odense University Hospital, Denmark. Electronic address:

Recent epidemiological studies have shown that, in addition to disease-specific effects, vaccines against infectious diseases have nonspecific effects on the ability of the immune system to handle other pathogens. For instance, in randomized trials tuberculosis and measles vaccines are associated with a substantial reduction in overall child mortality, which cannot be explained by prevention of the target disease. New research suggests that the nonspecific effects of vaccines are related to cross-reactivity of the adaptive immune system with unrelated pathogens, and to training of the innate immune system through epigenetic reprogramming. Hence, epidemiological findings are backed by immunological data. This generates a new understanding of the immune system and about how it can be modulated by vaccines to impact the general resistance to disease.
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http://dx.doi.org/10.1016/j.it.2013.04.004DOI Listing
September 2013

Anti-IFN-γ and peptide-tolerization therapies inhibit acute lung injury induced by cross-reactive influenza A-specific memory T cells.

J Immunol 2013 Mar 13;190(6):2736-46. Epub 2013 Feb 13.

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Viral infections have variable outcomes, with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with influenza A virus (IAV) and in memory phase challenged with lymphocytic choriomeningitis virus (LCMV), which we show in this study to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients who died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1703- and IAV-PA224-specific responses, which cross-reacted with LCMV-GP34 and LCMV-GP276, respectively. Eradication or functional ablation of these pathogenic memory T cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFN-γ treatment, inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology.
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http://dx.doi.org/10.4049/jimmunol.1201936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594402PMC
March 2013

Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope.

PLoS Pathog 2012 19;8(4):e1002633. Epub 2012 Apr 19.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

T cell cross-reactivity between different strains of the same virus, between different members of the same virus group, and even between unrelated viruses is a common occurrence. We questioned here how an intervening infection with a virus containing a sub-dominant cross-reactive T cell epitope would affect protective immunity to a previously encountered virus. Pichinde virus (PV) and lymphocytic choriomeningitis virus (LCMV) encode subdominant cross-reactive NP₂₀₅₋₂₁₂ CD8 T cell epitopes sharing 6 of 8 amino acids, differing only in the MHC anchoring regions. These pMHC epitopes induce cross-reactive but non-identical T cell receptor (TCR) repertoires, and structural studies showed that the differing anchoring amino acids altered the conformation of the MHC landscape presented to the TCR. PV-immune mice receiving an intervening infection with wild type but not NP205-mutant LCMV developed severe immunopathology in the form of acute fatty necrosis on re-challenge with PV, and this pathology could be predicted by the ratio of NP205-specific to the normally immunodominant PV NP₃₈₋₄₅-specific T cells. Thus, cross-reactive epitopes can exert pathogenic properties that compromise protective immunity by impairing more protective T cell responses.
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http://dx.doi.org/10.1371/journal.ppat.1002633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334890PMC
August 2012

Natural killer cells act as rheostats modulating antiviral T cells.

Nature 2011 Nov 20;481(7381):394-8. Epub 2011 Nov 20.

Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.

Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus-infected cells may contribute to antiviral defence during some virus infections--especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans--NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.
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http://dx.doi.org/10.1038/nature10624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539796PMC
November 2011

Computer simulations of heterologous immunity: highlights of an interdisciplinary cooperation.

Autoimmunity 2011 Jun 27;44(4):304-14. Epub 2011 Jan 27.

Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

The relationship between biological research and mathematical modeling is complex, critical, and vital. In this review, we summarize the results of the collaboration between two laboratories, exploring the interaction between mathematical modeling and wet-lab immunology. During this collaboration several aspects of the immune defence against viral infections were investigated, focusing primarily on the subject of heterologous immunity. In this manuscript, we emphasize the topics where computational simulations were applied in conjunction with experiments, such as immune attrition, the growing and shrinking of cross-reactive T cell repertoires following repeated infections, the short and long-term effects of cross-reactive immunological memory, and the factors influencing the appearance of new clonal specificities. For each topic, we describe how the mathematical model used was adapted to answer specific biological questions, and we discuss the hypotheses that were generated by simulations. Finally, we propose rules for testing hypotheses that emerge from model experimentation in the wet lab, and vice-versa.
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http://dx.doi.org/10.3109/08916934.2010.523220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633596PMC
June 2011

Heterologous immunity: immunopathology, autoimmunity and protection during viral infections.

Autoimmunity 2011 Jun 20;44(4):328-47. Epub 2011 Jan 20.

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Heterologous immunity is a common phenomenon present in all infections. Most of the time it is beneficial, mediating protective immunity, but in some individuals that have the wrong crossreactive response it leads to a cascade of events that result in severe immunopathology. Infections have been associated with autoimmune diseases such as diabetes, multiple sclerosis and lupus erythematosis, but also with unusual autoimmune like pathologies where the immune system appears dysregulated, such as, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans, infectious mononucleosis and even chronic fatigue syndrome. Here we review the evidence that to better understand these autoreactive pathologies it requires an evaluation of how T cells are regulated and evolve during sequential infections with different pathogens under the influence of heterologous immunity.
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http://dx.doi.org/10.3109/08916934.2011.523277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633594PMC
June 2011

Systematic simulation of cross-reactivity predicts ambiguity in Tk memory: it may save lives of the infected, but limits specificities vital for further responses.

Autoimmunity 2011 Jun 14;44(4):315-27. Epub 2011 Jan 14.

Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

The present study uses the agent-based model IMMSIM to simulate immune responses to a viral infection, with a focus on the impact of preformed memory (homologous and heterologous) on the quality and the efficacy of the response. The in machina results confirm the observed thwarting of new, naïve responses exerted by cross-reacting memory, but they also reveal that the competitive inhibition is made possible by the different time frame used by the primary and the secondary response, a well-known fact, epitomized by the interval of about 75 time steps between their peaks. This novel finding justifies the depression of naïve responses and the long-term consequences it could bring about and the role of memory as a player in a survival of the fittest game.
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http://dx.doi.org/10.3109/08916934.2011.523275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703517PMC
June 2011

A mucosal vaccination approach for herpes simplex virus type 2.

Vaccine 2011 Jan 4;29(5):1090-8. Epub 2010 Dec 4.

Biomedical Research Models, Inc., 67 Millbrook Street, Suite 422, Worcester, MA 01606, USA.

An estimated 1 out of every 5 Americans is infected with herpes simplex virus type 2 (HSV-2). Efforts in developing a potent vaccine for HSV-2 have shown limited success. Here we describe a heterologous vaccination strategy for HSV-2 based on an intramuscular DNA prime followed by a liposome-encapsulated antigen boost delivered intranasally. Both portions of the vaccine express the immunogenic HSV-2 glycoprotein D. In female Balb/c mice, this heterologous immunisation regimen stimulated high titers of serum neutralising antibodies, a DNA priming dose dependent T helper type response, enhanced mucosal immune responses and potent protective immunity at the portal of entry for the virus: the vaginal cavity. A clear synergistic effect on immune responses and protection from infection was seen using this heterologous immunisation approach. Suboptimal DNA prime (0.5 μg) followed by the liposome boost resulted in an 80% survival rate when mice were infected 2 weeks after immunisation. A higher dose of DNA priming (5 μg) followed by the liposome boost resulted in sterilising immunity in 80% of mice. The vaccine induced durable protection in mice, demonstrated by a 60% survival rate when lethal infections were performed 20 weeks after the immunisation primed with 0.5 μg of DNA vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2010.11.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035179PMC
January 2011

Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes.

J Immunol 2010 Dec 3;185(11):6753-64. Epub 2010 Nov 3.

Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Memory T cells cross-reactive with epitopes encoded by related or even unrelated viruses may alter the immune response and pathogenesis of infection by a process known as heterologous immunity. Because a challenge virus epitope may react with only a subset of the T cell repertoire in a cross-reactive epitope-specific memory pool, the vigorous cross-reactive response may be narrowly focused, or oligoclonal. We show in this article, by examining human T cell cross-reactivity between the HLA-A2-restricted influenza A virus-encoded M1(58-66) epitope (GILGFVFTL) and the dissimilar Epstein-Barr virus-encoded BMLF1(280-288) epitope (GLCTLVAML), that, under some conditions, heterologous immunity can lead to a significant broadening, rather than a narrowing, of the TCR repertoire. We suggest that dissimilar cross-reactive epitopes might generate a broad, rather than a narrow, T cell repertoire if there is a lack of dominant high-affinity clones; this hypothesis is supported by computer simulation.
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http://dx.doi.org/10.4049/jimmunol.1000812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738202PMC
December 2010

Bi-specific MHC heterodimers for characterization of cross-reactive T cells.

J Biol Chem 2010 Oct 20;285(43):33144-33153. Epub 2010 Aug 20.

From the Department of Pathology, Worcester, Massachusetts 01655; Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655. Electronic address:

T cell cross-reactivity describes the phenomenon whereby a single T cell can recognize two or more different peptide antigens presented in complex with MHC proteins. Cross-reactive T cells have previously been characterized at the population level by cytokine secretion and MHC tetramer staining assays, but single-cell analysis is difficult or impossible using these methods. In this study, we describe development of a novel peptide-MHC heterodimer specific for cross-reactive T cells. MHC-peptide monomers were independently conjugated to hydrazide or aldehyde-containing cross-linkers using thiol-maleimide coupling at cysteine residues introduced into recombinant MHC heavy chain proteins. Hydrazone formation provided bi-specific MHC heterodimers carrying two different peptides. Using this approach we prepared heterodimers of the murine class I MHC protein H-2K(b) carrying peptides from lymphocytic choriomeningitis virus and vaccinia virus, and used these to identify cross-reactive CD8+ T cells recognizing both lymphocytic choriomeningitis virus and vaccinia virus antigens. A similar strategy could be used to develop reagents to analyze cross-reactive T cell responses in humans.
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http://dx.doi.org/10.1074/jbc.M110.141051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963422PMC
October 2010

Heterologous immunity between viruses.

Immunol Rev 2010 May;235(1):244-66

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Immune memory responses to previously encountered pathogens can sometimes alter the immune response to and the course of infection of an unrelated pathogen by a process known as heterologous immunity. This response can lead to enhanced or diminished protective immunity and altered immunopathology. Here, we discuss the nature of T-cell cross-reactivity and describe matrices of epitopes from different viruses eliciting cross-reactive CD8(+) T-cell responses. We examine the parameters of heterologous immunity mediated by these cross-reactive T cells during viral infections in mice and humans. We show that heterologous immunity can disrupt T-cell memory pools, alter the complexity of the T-cell repertoire, change patterns of T-cell immunodominance, lead to the selection of viral epitope-escape variants, alter the pathogenesis of viral infections, and, by virtue of the private specificity of T-cell repertoires within individuals, contribute to dramatic variations in viral disease. We propose that heterologous immunity is an important factor in resistance to and variations of human viral infections and that issues of heterologous immunity should be considered in the design of vaccines.
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http://dx.doi.org/10.1111/j.0105-2896.2010.00897.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917921PMC
May 2010