Publications by authors named "Sneha Sant"

17 Publications

  • Page 1 of 1

Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients.

Nat Commun 2021 05 11;12(1):2691. Epub 2021 May 11.

Department of Biochemistry and Genetics, La Trobe Institute For Molecular Science, La Trobe University, Bundoora, VIC, Australia.

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 or CD4 T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23018-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113517PMC
May 2021

HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells.

PLoS Pathog 2020 08 4;16(8):e1008714. Epub 2020 Aug 4.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

Seasonal influenza virus infections cause 290,000-650,000 deaths annually and severe morbidity in 3-5 million people. CD8+ T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8+ T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified. These include HLA-A*02:01-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226, HLA-B*27:05-NP383-391 and HLA-B*57:01-NP199-207. The immunodominance hierarchies across these universal CD8+ T-cell epitopes were however unknown. Here, we probed immunodominance status of influenza-specific universal CD8+ T-cells in HLA-I heterozygote individuals expressing two or more universal HLAs for IAV. We found that while CD8+ T-cell responses directed towards A2/M158 were generally immunodominant, A2/M158+CD8+ T-cells were markedly diminished (subdominant) in HLA-A*02:01/B*27:05-expressing donors following ex vivo and in vitro analyses. A2/M158+CD8+ T-cells in non-HLA-B*27:05 individuals were immunodominant, contained optimal public TRBV19/TRAV27 TCRαβ clonotypes and displayed highly polyfunctional and proliferative capacity, while A2/M158+CD8+ T cells in HLA-B*27:05-expressing donors were subdominant, with largely distinct TCRαβ clonotypes and consequently markedly reduced avidity, proliferative and polyfunctional efficacy. Our data illustrate altered immunodominance patterns and immunodomination within human influenza-specific CD8+ T-cells. Accordingly, our work highlights the importance of understanding immunodominance hierarchies within individual donors across a spectrum of prominent virus-specific CD8+ T-cell specificities prior to designing T cell-directed vaccines and immunotherapies, for influenza and other infectious diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1008714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428290PMC
August 2020

Tissue-resident memory T cells in breast cancer control and immunotherapy responses.

Nat Rev Clin Oncol 2020 06 28;17(6):341-348. Epub 2020 Feb 28.

Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.

The presence of tumour-infiltrating lymphocytes (TILs) is associated with favourable outcomes in patients with breast cancer as well as in those with other solid tumours. T cells make up a considerable proportion of TILs and current evidence suggests that CD8 T cells are a crucial determinant of favourable clinical outcomes. Studies involving tumour material from numerous solid tumour types, including breast cancer, demonstrate that the CD8 TILs include a subpopulation of tissue-resident memory T (T) cells. This subpopulation has features consistent with those of T cells, which have been described as having a role in peripheral immune surveillance and viral immunity in both humans and mice. Patients with early-stage triple-negative breast cancers harbouring greater numbers of T cells have a substantially improved prognosis and longer overall survival. Furthermore, patients with advanced-stage breast cancers with higher levels of T cells have increased response rates to anti-PD-1 antibodies. These findings have motivated efforts to explore whether CD8 T cells include tumour-specific T cells, their functional responses to cognate antigens and their role in responses to immune checkpoint inhibition. In this Review, we focus on the clinical significance of CD8 T cells and the potential ways that these cells can be targeted to improve the success of immunotherapeutic approaches in patients with breast cancer, as well as in those with other solid tumour types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-020-0333-yDOI Listing
June 2020

Human Mucosal-Associated Invariant T Cells in Older Individuals Display Expanded TCRαβ Clonotypes with Potent Antimicrobial Responses.

J Immunol 2020 03 27;204(5):1119-1133. Epub 2020 Jan 27.

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia;

Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/effector memory-like profile that is sustained into older age. Whereas low-grade levels of plasma cytokine/chemokine were apparent in older donors (>65 y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older individuals and an aged environment resulted in the reversal of the baseline effector molecule profile comparable with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reduced -specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRαβ analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire diversity of virus-specific CD8 T cells. These data suggest that MAIT cells in older individuals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1900774DOI Listing
March 2020

Human γδ T-cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation.

Clin Transl Immunology 2019 23;8(9):e1079. Epub 2019 Sep 23.

Department of Microbiology and Immunology University of Melbourne at The Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia.

Background: Although γδ T cells comprise up to 10% of human peripheral blood T cells, questions remain regarding their role in disease states and T-cell receptor (TCR) clonal expansions. We dissected anti-viral functions of human γδ T cells towards influenza viruses and defined influenza-reactive γδ TCRs in the context of γδ-TCRs across the human lifespan.

Methods: We performed Cr-killing assay and single-cell time-lapse live video microscopy to define mechanisms underlying γδ T-cell-mediated killing of influenza-infected targets. We assessed cytotoxic profiles of γδ T cells in influenza-infected patients and IFN-γ production towards influenza-infected lung epithelial cells. Using single-cell RT-PCR, we characterised paired TCRγδ clonotypes for influenza-reactive γδ T cells in comparison with TCRs from healthy neonates, adults, elderly donors and tissues.

Results: We provide the first visual evidence of γδ T-cell-mediated killing of influenza-infected targets and show distinct features to those reported for CD8 T cells. γδ T cells displayed poly-cytotoxic profiles in influenza-infected patients and produced IFN-γ towards influenza-infected cells. These IFN-γ-producing γδ T cells were skewed towards the γ9δ2 TCRs, particularly expressing the public GV9-TCRγ, capable of pairing with numerous TCR-δ chains, suggesting their significant role in γδ T-cell immunity. Neonatal γδ T cells displayed extensive non-overlapping TCRγδ repertoires, while adults had enriched γ9δ2-pairings with diverse CDR3γδ regions. Conversely, the elderly showed distinct γδ-pairings characterised by large clonal expansions, a profile also prominent in adult tissues.

Conclusion: Human TCRγδ repertoire is shaped by age, tissue compartmentalisation and the individual's history of infection, suggesting that these somewhat enigmatic γδ T cells indeed respond to antigen challenge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cti2.1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756999PMC
September 2019

Divergent SATB1 expression across human life span and tissue compartments.

Immunol Cell Biol 2019 05 25;97(5):498-511. Epub 2019 Feb 25.

Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.

Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1). Thus, SATB1 expression in T-cell subsets across different tissue compartments in humans is of potential importance for targeting PD-1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD-1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen-specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T-cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine-tuned expression dynamics, which appear to be tissue- and antigen-dependent. Furthermore, SATB1 expression negatively correlates with PD-1 expression in virus-specific CD8 T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD-1 in T cells, highly relevant to human malignancies or chronic viral infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.12233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618325PMC
May 2019

Human CD8 T cell cross-reactivity across influenza A, B and C viruses.

Nat Immunol 2019 05 18;20(5):613-625. Epub 2019 Feb 18.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8 T cells confer cross-protection against IAV strains, however the responses of CD8 T cells to IBV and ICV are understudied. We investigated the breadth of CD8 T cell cross-recognition and provide evidence of CD8 T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8 T cell epitopes from IBVs that were protective in mice and found memory CD8 T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8 T cells displayed tissue-resident memory phenotypes. Notably, CD38Ki67CD8 effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8 T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41590-019-0320-6DOI Listing
May 2019

Broad CD8 T cell cross-recognition of distinct influenza A strains in humans.

Nat Commun 2018 12 21;9(1):5427. Epub 2018 Dec 21.

Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3010, Australia.

Newly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8 T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding of T-cell receptor (TCRαβ) cross-reactivity towards IAV variants is needed for a vaccine design. Here, we investigate TCRαβ cross-strain recognition across IAV variants within two immunodominant human IAV-specific CD8 T-cell epitopes, HLA-B*37:01-restricted NP (B37-NP) and HLA-A*01:01-restricted NP (A1-NP). We find high abundance of cross-reactive TCRαβ clonotypes recognizing distinct IAV variants. Structures of the wild-type and variant peptides revealed preserved conformation of the bound peptides. Structures of a cross-reactive TCR-HLA-B37-NP complex suggest that the conserved conformation of the variants underpins TCR cross-reactivity. Overall, cross-reactive CD8 T-cell responses, underpinned by conserved epitope structure, facilitates recognition of distinct IAV variants, thus CD8 T-cell-targeted vaccines could provide protection across different IAV strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07815-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303473PMC
December 2018

MAIT cells contribute to protection against lethal influenza infection in vivo.

Nat Commun 2018 11 9;9(1):4706. Epub 2018 Nov 9.

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia.

Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1 mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2γC mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07207-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226485PMC
November 2018

Single-Cell Approach to Influenza-Specific CD8 T Cell Receptor Repertoires Across Different Age Groups, Tissues, and Following Influenza Virus Infection.

Front Immunol 2018 27;9:1453. Epub 2018 Jun 27.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

CD8 T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8 T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8 T cells across anatomical sites and immunological phases of human life. We used peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M1 (A2M1). We dissected memory TCR repertoires directed toward A2M1 CD8 T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8 T cell repertoires to A2M1 CD8 TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first comparative analysis of paired antigen-specific TCR-α/β clonotypes across different tissues and peripheral blood across different age groups. We show that human A2M1 CD8 T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2M1 TCRαβ repertoires reflect A2M1 TCRαβ clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2M1 TCRαβ repertoires displayed distinct features only in elderly adults, with large private TCRαβ clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRαβ repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRαβ signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030351PMC
June 2018

Clonally diverse CD38HLA-DRCD8 T cells persist during fatal H7N9 disease.

Nat Commun 2018 02 26;9(1):824. Epub 2018 Feb 26.

Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, 201508, Shangai, China.

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8 T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38HLA-DRPD-1 CD8 T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αβ analyses of activated CD38HLA-DRCD8 T cells show similar TCRαβ diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38HLA-DRCD8 T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38HLA-DRCD8 T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαβ clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-03243-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827521PMC
February 2018

Circulating T cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity.

Sci Transl Med 2018 02;10(428)

Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.

Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (T) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5CXCR3 antibody-secreting B cell population, CD21CD27 memory B cells, and CD21CD27 B cells. Activation of circulating T cells correlated with the development of both CD21 and CD21 memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8, mucosal-associated invariant T, γδ T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21CD27) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating T cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aan8405DOI Listing
February 2018

Innate and adaptive T cells in influenza disease.

Front Med 2018 Feb 20;12(1):34-47. Epub 2018 Jan 20.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, 3010, Victoria, Australia.

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses. Moreover, vaccines designed to generate influenza-specific T-cell responses are yet to be optimized. During natural infection, viral replication is initially controlled by innate immunity before adaptive immune responses (T cells and antibody-producing B cells) achieve viral clearance and host recovery. Adaptive T and B cells maintain immunological memory and provide protection against subsequent infections with related influenza viruses. Recent studies also shed light on the role of innate T-cells (MAIT cells, γδ cells, and NKT cells) in controlling influenza and linking innate and adaptive immune mechanisms, thus making them attractive targets for vaccination strategies. We summarize the current knowledge on influenza-specific innate MAIT and γδ T cells as well as adaptive CD8 and CD4 T cells, and discuss how these responses can be harnessed by novel vaccine strategies to elicit cross-protective immunity against different influenza strains and subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11684-017-0606-8DOI Listing
February 2018

Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles.

J Clin Invest 2018 02 8;128(2):721-733. Epub 2018 Jan 8.

Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8+ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8+ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus-specific CD8+ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8+ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza-specific CD8+ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8+ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI96957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785253PMC
February 2018

Perturbed CD8 T cell immunity across universal influenza epitopes in the elderly.

J Leukoc Biol 2018 02 29;103(2):321-339. Epub 2017 Dec 29.

Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

Influenza epidemics lead to severe illness, life-threatening complications, and deaths, especially in the elderly. As CD8 T cells are associated with rapid recovery from influenza, we investigated the effects of aging on antigen-specific CD8 T cells across the universal influenza epitopes in humans. We show that aging is characterized by altered frequencies in T cell subsets, with naive T cells being partially replaced by activated effector/memory populations. Although we observed no striking differences in TCR signaling capacity, T cells in the elderly had increased expression of transcription factors Eomes and T-bet, and such changes were most apparent in CD8 T cells. Strikingly, the numbers of antigen-specific CD8 T cells across universal influenza epitopes were reduced in the elderly, although their effector/memory phenotypes remained stable. To understand whether diminished numbers of influenza-specific CD8 T cells in the elderly resulted from alteration in TCR clonotypes, we dissected the TCRαβ repertoire specific for the prominent HLA-A*02:01-restricted-M1 (A2/M1 ) influenza epitope. We provide the first ex vivo data on paired antigen-specific TCRαβ clonotypes in the elderly, showing that influenza-specific A2/M1 TCRαβ repertoires in the elderly adults varied from those in younger adults, with the main features being a reduction in the frequency of the public TRAV27-TRBV19 TCRαβ clonotype, increased proportion of private TCRαβ signatures, broader use of TRAV and TRBV gene segments, and large clonal expansion of private TCRαβ clonotypes with longer CDR3 loops. Our study supports the development of T cell-targeted influenza vaccines that would boost the T cell compartment during life and maintain the numbers and optimal TCRαβ signatures in the elderly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1189/jlb.5MA0517-207RDOI Listing
February 2018

The role of CD27 in anti-viral T-cell immunity.

Curr Opin Virol 2017 02 12;22:77-88. Epub 2017 Jan 12.

Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne 3000, VIC, Australia. Electronic address:

CD27 is a co-stimulatory immune-checkpoint receptor, constitutively expressed on a broad range of T-cells (αβ and γδ), NK-cells and B-cells. Ligation of CD27 with CD70 results in potent co-stimulatory effects. In mice, co-stimulation of CD8 T-cells through CD27 promotes immune activation and enhances primary, secondary, memory and recall responses towards viral infections. Limited in vitro human studies support mouse experiments and show that CD27 co-stimulation enhances antiviral T-cell immunity. Given the potent co-stimulatory effects of CD27, manipulating CD27 signalling is of interest for viral, autoimmune and anti-tumour immunotherapies. This review focuses on the role of CD27 co-stimulation in anti-viral T-cell immunity and discusses clinical studies utilising the CD27 co-stimulation pathway for anti-viral, anti-tumour and autoimmune immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coviro.2016.12.001DOI Listing
February 2017

Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation.

Proc Natl Acad Sci U S A 2016 09 19;113(36):10133-8. Epub 2016 Aug 19.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)Vα7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1610750113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018778PMC
September 2016
-->