Publications by authors named "Laura A Vella"

24 Publications

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Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

Sci Immunol 2021 03;6(57)

Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.
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http://dx.doi.org/10.1126/sciimmunol.abf7570DOI Listing
March 2021

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

Cell 2021 04 9;184(7):1858-1864.e10. Epub 2021 Feb 9.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.cell.2021.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871851PMC
April 2021

The Identity of Human Tissue-Emigrant CD8 T Cells.

Cell 2020 Dec 10;183(7):1946-1961.e15. Epub 2020 Dec 10.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8 T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8 T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8 T cells that recirculate via TDL.
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http://dx.doi.org/10.1016/j.cell.2020.11.019DOI Listing
December 2020

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

Blood Adv 2020 12;4(23):6051-6063

Immune Dysregulation Frontier Program, Department of Pediatrics.

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.
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http://dx.doi.org/10.1182/bloodadvances.2020003471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724906PMC
December 2020

SARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-19.

J Pediatric Infect Dis Soc 2020 Dec 2. Epub 2020 Dec 2.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.

SARS-CoV-2 antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients.
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http://dx.doi.org/10.1093/jpids/piaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799010PMC
December 2020

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

medRxiv 2020 Nov 10. Epub 2020 Nov 10.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the COVID-19 pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 204 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 252 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼23% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically these hCoV cross-reactive antibodies were boosted upon SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.11.06.20227215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668756PMC
November 2020

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

Pediatr Blood Cancer 2020 11 4;67(11):e28693. Epub 2020 Sep 4.

Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.
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http://dx.doi.org/10.1002/pbc.28693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734626PMC
November 2020

SARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-19.

medRxiv 2020 Aug 18. Epub 2020 Aug 18.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.

SARS-CoV-2 antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients.
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http://dx.doi.org/10.1101/2020.08.17.20176552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444298PMC
August 2020

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

J Clin Invest 2020 11;130(11):5967-5975

Immune Dysregulation Frontier Program.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.
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http://dx.doi.org/10.1172/JCI140970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598044PMC
November 2020

SARS-CoV-2 seroprevalence among parturient women in Philadelphia.

Sci Immunol 2020 07;5(49)

Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Limited data are available for pregnant women affected by SARS-CoV-2. Serological tests are critically important for determining SARS-CoV-2 exposures within both individuals and populations. We validated a SARS-CoV-2 spike receptor binding domain serological test using 834 pre-pandemic samples and 31 samples from COVID-19 recovered donors. We then completed SARS-CoV-2 serological testing of 1,293 parturient women at two centers in Philadelphia from April 4 to June 3, 2020. We found 80/1,293 (6.2%) of parturient women possessed IgG and/or IgM SARS-CoV-2-specific antibodies. We found race/ethnicity differences in seroprevalence rates, with higher rates in Black/non-Hispanic and Hispanic/Latino women. Of the 72 seropositive women who also received nasopharyngeal polymerase chain reaction testing during pregnancy, 46 (64%) were positive. Continued serologic surveillance among pregnant women may inform perinatal clinical practices and can potentially be used to estimate exposure to SARS-CoV-2 within the community.
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http://dx.doi.org/10.1126/sciimmunol.abd5709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594018PMC
July 2020

SARS-CoV-2 Seroprevalence Among Parturient Women.

medRxiv 2020 Jul 10. Epub 2020 Jul 10.

Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Limited data are available for pregnant women affected by SARS-CoV-2. Serological tests are critically important to determine exposure and immunity to SARS-CoV-2 within both individuals and populations. We completed SARS-CoV-2 serological testing of 1,293 parturient women at two centers in Philadelphia from April 4 to June 3, 2020. We tested 834 pre-pandemic samples collected in 2019 and 15 samples from COVID-19 recovered donors to validate our assay, which has a ~1% false positive rate. We found 80/1,293 (6.2%) of parturient women possessed IgG and/or IgM SARS-CoV-2-specific antibodies. We found race/ethnicity differences in seroprevalence rates, with higher rates in Black/non-Hispanic and Hispanic/Latino women. Of the 72 seropositive women who also received nasopharyngeal polymerase chain reaction testing during pregnancy, 46 (64%) were positive. Continued serologic surveillance among pregnant women may inform perinatal clinical practices and can potentially be used to estimate seroprevalence within the community.
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http://dx.doi.org/10.1101/2020.07.08.20149179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359548PMC
July 2020

Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications.

Science 2020 09 15;369(6508). Epub 2020 Jul 15.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.
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http://dx.doi.org/10.1126/science.abc8511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402624PMC
September 2020

Comprehensive mapping of immune perturbations associated with severe COVID-19.

Sci Immunol 2020 07;5(49)

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.
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http://dx.doi.org/10.1126/sciimmunol.abd7114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402634PMC
July 2020

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions.

bioRxiv 2020 May 23. Epub 2020 May 23.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine.

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ~200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.
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http://dx.doi.org/10.1101/2020.05.20.106401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263500PMC
May 2020

TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision.

Immunity 2019 11 9;51(5):840-855.e5. Epub 2019 Oct 9.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1Ly108PD-1 CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1 effectors while fostering KLRG1 Tex precursor cells, and PD-1 stabilized this TCF-1 Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.
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http://dx.doi.org/10.1016/j.immuni.2019.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943829PMC
November 2019

T follicular helper cells in human efferent lymph retain lymphoid characteristics.

J Clin Invest 2019 07 2;129(8):3185-3200. Epub 2019 Jul 2.

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.
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http://dx.doi.org/10.1172/JCI125628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668682PMC
July 2019

The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.

Dev Cell 2019 04 28;49(1):10-29. Epub 2019 Mar 28.

Department of Biomedical Informatics, University of Cincinnati College of Medicine, and Cincinnati Children's Hospital Medical Center, Division of Biomedical Informatics, Cincinnati, OH 45229, USA.

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.
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http://dx.doi.org/10.1016/j.devcel.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616346PMC
April 2019

Identification and characterization of HIV-specific resident memory CD8 T cells in human lymphoid tissue.

Sci Immunol 2018 06;3(24)

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Current paradigms of CD8 T cell-mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8 T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (T). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8 T cells in LTs also resemble T Moreover, high frequencies of HIV-specific CD8 T with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific T are enriched for effector-related immune genes and signatures compared with HIV-specific non-T in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8 T cell responses resident within LTs.
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http://dx.doi.org/10.1126/sciimmunol.aar4526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357781PMC
June 2018

Spatial distribution and function of T follicular regulatory cells in human lymph nodes.

J Exp Med 2018 06 16;215(6):1531-1542. Epub 2018 May 16.

Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH

T follicular regulatory (Tfr) cells are a population of CD4 T cells that express regulatory T cell markers and have been shown to suppress humoral immunity. However, the precise mechanisms and location of Tfr-mediated suppression in the lymph node (LN) microenvironment are unknown. Using highly multiplexed quantitative imaging and functional assays, we examined the spatial distribution, suppressive function, and preferred interacting partners of Tfr cells in human mesenteric LNs. We find that the majority of Tfr cells express low levels of PD-1 and reside at the border between the T cell zone and B cell follicle, with very few found in the germinal centers (GCs). Although PD-1 Tfr cells expressed higher levels of CD38, CTLA-4, and GARP than PD-1 Tfr cells, both potently suppressed antibody production in vitro. These findings highlight the phenotypic diversity of human Tfr cells and suggest that Tfr-mediated suppression is most efficient at the T-B border and within the follicle, not in the GC.
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http://dx.doi.org/10.1084/jem.20171940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987920PMC
June 2018

CD4 T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective.

Trends Mol Med 2017 12 12;23(12):1072-1087. Epub 2017 Nov 12.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address:

CD4 T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4 T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4 T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8 T cells as well. In this review, we discuss what is known about CD4 T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.
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http://dx.doi.org/10.1016/j.molmed.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886740PMC
December 2017

The Cost of a Culture and Doctoring at a Distance.

Hosp Pediatr 2015 Nov;5(11):597-9

General Pediatrics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia Pennsylvania; and Perelman School of Medicine at the University of Pennsylvania, Philadelphia Pennsylvania.

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http://dx.doi.org/10.1542/hpeds.2015-0083DOI Listing
November 2015

Immunity against cyclin B1 tumor antigen delays development of spontaneous cyclin B1-positive tumors in p53 (-/-) mice.

Ann N Y Acad Sci 2009 Sep;1174:68-73

Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

We previously identified cyclin B1-specific T cells and antibodies in cancer patients with cyclin B1-positive (+) tumors and also in some healthy individuals. We also demonstrated that these responses may be important in cancer immunosurveillance by showing that vaccination against cyclin B1 prevents growth of transplantable cyclin B1(+) tumors in mice. Constitutive overexpression of cyclin B1 was determined to correlate with the lack of p53 function. This allowed us to use p53(-/-) mice as a model that better approximates human disease. These p53(-/-) mice spontaneously develop cyclin B1(+) tumors. At 5-6 weeks of age, when the mice were still healthy with no evidence of tumor, they received the cyclin B1 vaccine and were then observed for tumor growth. We demonstrate that cyclin B1 vaccination delays spontaneous cyclin B1(+) tumor growth and increases median survival of tumor-bearing p53(-/-) mice.
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http://dx.doi.org/10.1111/j.1749-6632.2009.04941.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472441PMC
September 2009

Healthy individuals have T-cell and antibody responses to the tumor antigen cyclin B1 that when elicited in mice protect from cancer.

Proc Natl Acad Sci U S A 2009 Aug 3;106(33):14010-5. Epub 2009 Aug 3.

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

We previously identified the aberrantly expressed cell cycle regulator cyclin B1 as a tumor antigen recognized by antibodies and T cells from patients with breast, lung, and head and neck cancers. Ordinarily expressed only transiently in the G2/M stage of the cell cycle in normal cells, cyclin B1 is constitutively expressed at high levels in the cytoplasm of these and many other tumor types, leading to its recognition by the cancer patient's immune system. We report here an unexpected observation that cyclin B1-specific antibody and memory CD4 and CD8 T cells are also found in many healthy individuals who have no history of cancer. Moreover, young as well as older healthy people have these responses suggesting that events other than cancer, which occur either early in life or throughout life, may lead to aberrant cyclin B1 expression and anti-cyclin B1 immunity. The role, if any, of immunity to this tumor-associated antigen is not known. We wanted to determine specifically whether immunity to cyclin B1 might be important in the immunosurveillance of cyclin B1+ tumors. We therefore tested in mice the effectiveness of vaccine-elicited anti-cyclin B1 immunity against a cyclin B1+ mouse tumor that was chosen based on our published observation that cyclin B1 overexpression is associated with the lack of p53 function. We found that cyclin B1 DNA prime-protein boost vaccine protected mice from a challenge with a tumor cell line that was established from a tumor arising in the p53(-/-) mouse that spontaneously overexpresses cyclin B1.
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http://dx.doi.org/10.1073/pnas.0903225106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720407PMC
August 2009

Cyclin B1 and other cyclins as tumor antigens in immunosurveillance and immunotherapy of cancer.

Cancer Res 2006 Jan;66(1):6-9

Department of Immunology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

Uncontrolled cell division is an indispensable event in tumor progression, and numerous molecules involved in this process have been the focus of intense investigation in tumor biology. Cyclins, molecules that orchestrate normal cell cycle progression, are abnormally overexpressed in various human cancers. We review evidence that the immune system recognizes some abnormally expressed cyclins as tumor antigens, such as cyclin B1, and we analyze the potential of cyclins D, E, and A to serve a similar function in cancer immunosurveillance.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-3389DOI Listing
January 2006