scholarly journals Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

2016 ◽  
Vol 113 (41) ◽  
pp. E6192-E6198 ◽  
Author(s):  
Laura F. Su ◽  
Daniel del Alcazar ◽  
Erietta Stelekati ◽  
E. John Wherry ◽  
Mark M. Davis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
T Cell Subsets ◽  
Major Influence ◽  
Cell Phenotype ◽  
Antigen Specificity ◽  
Cell Repertoire

The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide–MHC tetramers, we isolated rare specific Foxp3+ cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive Tregs in the absence of cognate infection. In contrast, the frequencies of Tregs that recognize some common microbial antigens are significantly reduced in the blood of most adults. Exposure to peripheral antigens likely has a major influence on the balance between Tregs and conventional T-cell subsets because a larger proportion of flu-specific T cells has a regulatory cell phenotype in the cord blood. Consistent with this finding, we show that lymphocytic choriomeningitis virus infection can directly modulate the ratio of virus-specific effectors and Tregs in mice. The resulting change in the balance within an antigen-specific T-cell population further correlates with the magnitude of effector response and the chronicity of infection. Taken together, our data highlight the importance of antigen specificity in the functional dynamics of the T-cell repertoire. Each specific population of CD4+ T cells in human peripheral blood contains a subset of Tregs at birth, but the balance between regulatory and effector subsets changes in response to peripheral antigen exposure and this could impact the robustness of antipathogen immunity.

Age-related increase of frequency of a new, phenotypically distinct subpopulation of human peripheral blood T cells expressing lowered levels of CD4

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1100-1107 ◽  
Author(s):  
Ewa Bryl ◽  
Magdalena Gazda ◽  
Jerzy Foerster ◽  
Jacek M. Witkowski
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
The Elderly ◽  
Cell Subpopulation ◽  
Cell Phenotype ◽  
Receptor Complexes ◽  
Age Related

Aging is associated with modifications of T-cell phenotype and function, leading to impaired activation in response to both new and recall antigens. It is not known if T-cell activation results in elimination of a number of the CD4 molecules from the cell surface, as is the case with CD3/T-cell receptor complexes, or how aging influences the process. The T cells of young and elderly donors with reduced expression of CD4 were examined to see whether these cells exhibit other phenotypic features suggesting their active state. It was found that T lymphocytes expressing CD4 can be divided into 2 semidiscrete subpopulations: the major (CD4+) population, in which the level of expression of CD4 is constant and high, and a minor population (CD4lo), in which the expression of CD4 can be up to an order of magnitude lower than on the CD4+ cells. The proportion of CD4locells is age dependent and highly variable in the apparently healthy human population, with the expression of CD4 ranging from around 10% of all peripheral blood lymphocytes in the young to more than 30% in the elderly. Lowered expression of CD4 is correlated with a reduced expression of CD3, as well as with a decreased amount of CD28 and CD95Fas. Activation of CD4lo cells is suggested by their expression of CD25 and increased amounts of HLA-DR. Phenotypic characteristics of the CD4lo T-cell subpopulation suggest that it might be formed by (perhaps chronically) activated, temporarily apoptosis-resistant cells, possibly accumulating in the elderly.

Numeration of T Cell Subsets in Sarcoidosis Using Monoclonal Antibodies: Decreased Levels of Peripheral Blood T Cells and Cells with Suppressor T Cell Phenotype

Dermatology ◽  
1982 ◽  
Vol 165 (2) ◽  
pp. 88-93 ◽  
Author(s):  
Michel Faure ◽  
Jean-Francois Nicolas ◽  
Martine Gaucherand ◽  
Janusz Czernielewski ◽  
Gilles Mauduit ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Suppressor T Cell

CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T-cell subsets involved in transplant acceptance

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3936-3948 ◽  
Author(s):  
Abderrahim Naji ◽  
Solene Le Rond ◽  
Antoine Durrbach ◽  
Irene Krawice-Radanne ◽  
Caroline Creput ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Plasma Concentrations ◽  
Suppressor Cells ◽  
Peripheral Tolerance ◽  
T Cell Subsets ◽  
Hla Dr ◽  
Antigen Presenting

Abstract HLA-G is a tolerogenic molecule whose detection in sera and within allografted tissues is associated with better graft acceptance. HLA-G mediates T-cell differentiation into suppressor cells, which are thought to promote tolerance. Here, we investigated such T cells phenotypically and functionally and assessed their clinical relevance in the peripheral blood of patients who have undergone transplantation. Our results demonstrate that HLA-G expressed by antigen-presenting cells or present as soluble protein down-regulates the expression of CD4 and CD8 on allostimulated T cells at both transcriptional and posttranslational levels. These CD3+CD4low and CD3+CD8low T-cell subsets are characterized by an increased proportion of cells expressing CD45RA and HLA-DR, and a decreased number of cells expressing CD62L. In addition, these HLA-G–induced CD3+CD4low and CD3+CD8low subpopulations are Foxp3-negative suppressor T cells whose function involves IL-10. Biologic relevance came from analysis of patients who underwent transplantation, with high HLA-G plasma concentrations associated with better graft survival. Peripheral blood from these patients contains increased levels of IL-10 concomitantly to an enhanced representation of CD3+CD4low and CD3+CD8low T cells compared with HLA-G–negative patients who underwent transplantation and healthy individuals. These data define novel immunosuppressive subpopulations of peripheral blood T cells induced by HLA-G with potent implications in peripheral tolerance.

scholarly journals Comprehensive analysis of structural and sequencing data reveals almost unconstrained chain pairing in TCRαβ complex

2019 ◽  
Author(s):  
Dmitrii S Shcherbinin ◽  
Vlad A Belousov ◽  
Mikhail Shugay
Keyword(s):  
T Cells ◽  
T Cell ◽  
Structural Data ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Sequencing Data ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Effective Response ◽  
Specific Choice

AbstractAntigen recognition by T-cells is guided by the T-cell receptor (TCR) heterodimer formed by α and β chains. A huge diversity of TCR sequences should be maintained by the immune system in order to be able to mount an effective response towards foreign pathogens, so, due to cooperative binding of α and β chains to the pathogen, any constraints on chain pairing can have a profound effect on immune repertoire structure, diversity and antigen specificity. By integrating available structural data and paired chain sequencing results we were able to show that there are almost no constraints on pairing in TCRαβ complexes, allowing naive T-cell repertoire to reach the highest possible diversity. Additional analysis reveals that the specific choice of contacting amino acids can still have a profound effect on complex conformation. Moreover, antigen-driven selection can distort the uniform landscape of chain pairing, while small, yet significant, differences in the pairing can be attributed to various specialized T-cell subsets such as MAIT and iNKT T-cells, as well as other putative invariant TCRs.

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

scholarly journals Quantitative assessment of the pool size and subset distribution of cytolytic T lymphocytes within human resting or alloactivated peripheral blood T cell populations.

1983 ◽  
Vol 158 (2) ◽  
pp. 571-585 ◽  
Author(s):  
A Moretta ◽  
G Pantaleo ◽  
L Moretta ◽  
M C Mingari ◽  
J C Cerottini
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Great Majority ◽  
T Cell Subsets ◽  
Cytolytic T Lymphocytes ◽  
Subset Distribution

In order to directly assess the distribution of cytolytic T lymphocytes (CTL) and their precursors (CTL-P) in the two major subsets of human T cells, we have used limiting dilution microculture systems to determine their frequencies. The two subsets were defined according to their reactivity (or lack thereof) with B9.4 monoclonal antibody (the specificity of which is similar, if not identical, to that of Leu 2b monoclonal antibody). Both B9+ and B9- cells obtained by sorting peripheral blood resting T cells using the fluorescence-activated cell sorter (FACS) were assayed for total CTL-P frequencies in a microculture system that allows clonal growth of every T cell. As assessed by a lectin-dependent assay, approximately 30% of peripheral blood T cells were CTP-P. In the B9+ subset (which represents 20-30% of all T cells), the CTL-P frequency was close to 100%, whereas the B9- subset had a 25-fold lower CTL-P frequency. It is thus evident that 90% and 10% of the total CTL-P in peripheral blood are confined to the B9+ or B9- T cell subsets, respectively. Analysis of the subset distribution of CTL-P directed against a given set of alloantigens confirmed these findings. CTL-P frequencies were also determined in B9+ and B9- subsets derived from T cells that had been activated in allogenic mixed leucocyte cultures (MLC). Approximately 10% of MLC T cells were CTL-P. This frequency was increased 3.5-fold in the B9+ subset, whereas the B9- subset contained only a small, although detectable number of CTL-P. Moreover, the great majority of the (operationally defined) CTL-P in MLC T cell population were found to be directed against the stimulating alloantigens, thus indicating a dramatic increase in specific CTL-P frequencies following in vitro stimulation in bulk cultures.

scholarly journals Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sofya A Kasatskaya ◽  
Kristin Ladell ◽  
Evgeniy S Egorov ◽  
Kelly L Miners ◽  
Alexey N Davydov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptors ◽  
Adaptive Immune System ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Intrinsic Properties ◽  
Antigen Specificity ◽  
Adaptive Immune ◽  
Transition Pathways

The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

scholarly journals Inconsistent Reversal of HIV-1 Latency Ex Vivo by Antigens of HIV-1, CMV, and Other Infectious Agents

2020 ◽  
Author(s):  
Thomas Vollbrecht ◽  
Aaron O. Angerstein ◽  
Bryson Menke ◽  
Nikesh M. Kumar ◽  
Michelli Faria Oliveira ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Latent Reservoir ◽  
Antigen Specificity ◽  
Pcr Assay ◽  
Hiv 1

Abstract BackgroundA reservoir of replication-competent but latent virus is the main obstacle to a cure for HIV-infection. Much of this reservoir resides in memory CD4 T cells. We hypothesized that these cells can be reactivated with antigens from HIV and other common pathogens to reverse latency. ResultsWe obtained mononuclear cells from the peripheral blood of antiretroviral-treated patients with suppressed viremia. We tested pools of peptides and proteins derived from HIV and from other pathogens including CMV for their ability to reverse latency ex vivo by activation of memory responses. We assessed activation of the CD4 T cells by measuring the up-regulation of cell-surface CD69. We assessed HIV-expression using two assays: a real-time PCR assay for virion-associated viral RNA and a droplet digital PCR assay for cell-associated, multiply spliced viral mRNA. Reversal of latency occurred in a minority of cells from some participants, but no single antigen induced HIV-expression ex vivo consistently. When reversal of latency was induced by a specific peptide pool or protein, the extent was proportionally greater than that of T cell activation. ConclusionsIn this group of patients in whom antiretroviral therapy was started during chronic infection, the latent reservoir does not appear to consistently reside in CD4 T cells of a predominant antigen-specificity. Peptide-antigens reversed HIV-latency ex vivo with modest and variable activity. When latency was reversed by specific peptides or proteins, it was proportionally greater than the extent of T cell activation, suggesting partial enrichment of the latent reservoir in cells of specific antigen-reactivity.

scholarly journals The human liver microenvironment shapes the homing and function of CD4+T-cell populations

2020 ◽  
Author(s):  
Benjamin G. Wiggins ◽  
Laura J. Pallett ◽  
Xiaoyan Li ◽  
Scott P. Davies ◽  
Oliver E. Amin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Liver ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
List Type ◽  
Cd69 Expression ◽  
Resident Memory T Cells

ABSTRACTBackground & AimsTissue-resident memory T cells (TRM) are important immune sentinels that provide efficient in situ immunity. Liver-resident CD8+ TRM have been previously described, and contribute to viral control in persistent hepatotropic infections. However, little is known regarding liver CD4+ TRM cells. Here we profiled resident and non-resident intrahepatic CD4+ T cell subsets, assessing their phenotype, function, differential generation requirements and roles in hepatotropic infection.MethodsLiver tissue was obtained from 173 subjects with (n=109) or without (n=64) hepatic pathology. Multiparametric flow cytometry and immunofluorescence imaging examined T cell phenotype, functionality and location. Liver T cell function was determined after stimulation with anti-CD3/CD28 and PMA/Ionomycin. Co-cultures of blood-derived lymphocytes with hepatocyte cell lines, primary biliary epithelial cells, and precision-cut autologous liver slices were used to investigate the acquisition of liver-resident phenotypes.ResultsCD69 expression delineated two distinct subsets in the human liver. CD69HI cells were identified as CD4+ TRM due to exclusion from the circulation, a residency-associated phenotype (CXCR6+CD49a+S1PR1-PD-1+), restriction to specific liver niches, and ability to produce robust type-1 multifunctional cytokine responses. Conversely, CD69INT were an activated T cell population also found in the peripheral circulation, with a distinct homing profile (CX3CR1+CXCR3+CXCR1+), and a bias towards IL-4 production. Frequencies of CD69INT cells correlated with the degree of fibrosis in chronic hepatitis B virus infection. Interaction with hepatic epithelia was sufficient to generate CD69INT cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HI cells.ConclusionsIntermediate and high CD69 expression demarcates two discrete intrahepatic CD4+ T cell subsets with distinct developmental and functional profiles.Graphical AbstractHighlightsCD69HI (CXCR6+CD49a+S1PR1-PD-1+) are the CD4+ TRM of the human liverHepatic CD69INTCD4+ T-cells are distinct, activated, and recirculation-competentStimulation evokes respective IFN-γ and IL-4 responses in CD69HI and CD69INT cellsCD69INT cell frequencies correlate with worsening fibrosis in chronic HBV patientsLiver slice cultures allow differentiation of CD69INT and CD69HI cells from bloodLay summaryTissue-resident memory T cells (TRM) orchestrate regional immune responses, but much of the biology of liver-resident CD4+ TRM remains unknown. We found high expression of cell-surface protein CD69 defined hepatic CD4+ TRM, while simultaneously uncovering a distinct novel recirculatory CD69INT CD4+ T cell subset. Both subsets displayed unique immune receptor profiles, were functionally skewed towards type-1 and type-2 responses respectively, and had distinct generation requirements, highlighting the potential for differential roles in the immunopathology of chronic liver diseases.

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