scholarly journals Targeted reconstruction of T cell receptor sequence from single cell RNA-sequencing links CDR3 length to T cell differentiation state

2016 ◽  
Author(s):  
Shaked Afik ◽  
Kathleen B. Yates ◽  
Kevin Bi ◽  
Samuel Darko ◽  
Jernej Godec ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cell Response ◽  
T Cell Response ◽  
Effector Memory ◽  
Cell State ◽  
Tcr Repertoire ◽  
Single Cell Rna Sequencing

ABSTRACTThe T cell compartment must contain diversity in both TCR repertoire and cell state to provide effective immunity against pathogens1,2. However, it remains unclear how differences in the TCR contribute to heterogeneity in T cell state at the single cell level because most analysis of the TCR repertoire has, to date, aggregated information from populations of cells. Single cell RNA-sequencing (scRNA-seq) can allow simultaneous measurement of TCR sequence and global transcriptional profile from single cells. However, current protocols to directly sequence the TCR require the use of long sequencing reads, increasing the cost and decreasing the number of cells that can be feasibly analyzed. Here we present a tool that can efficiently extract TCR sequence information from standard, short-read scRNA-seq libraries of T cells: TCR Reconstruction Algorithm for Paired-End Single cell (TRAPeS). We apply it to investigate heterogeneity in the CD8+T cell response in humans and mice, and show that it is accurate and more sensitive than previous approaches3,4. We applied TRAPeS to single cell RNA-seq of CD8+T cells specific for a single epitope from Yellow Fever Virus5. We show that the recently-described "naive-like" memory population of YFV-specific CD8+T cells have significantly longer CDR3 regions and greater divergence from germline sequence than do effector-memory phenotype CD8+T cells specific for YFV. This suggests that TCR usage contributes to heterogeneity in the differentiation state of the CD8+T cell response to YFV. TRAPeS is publicly available, and can be readily used to investigate the relationship between the TCR repertoire and cellular phenotype.

scholarly journals Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial

2020 ◽  
Vol 8 (2) ◽  
pp. e001157
Author(s):  
Juliane Schuhmacher ◽  
Sonja Heidu ◽  
Torben Balchen ◽  
Jennifer Rebecca Richardson ◽  
Camilla Schmeltz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Cell Response ◽  
Small Gtpase ◽  
T Cell Response ◽  
Effector Memory ◽  
Tolerability Profile

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

scholarly journals Heterogeneity of T Cells in Atherosclerosis Defined by Single-Cell RNA-Sequencing and Cytometry by Time of Flight

2020 ◽  
Author(s):  
Holger Winkels ◽  
Dennis Wolf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
T Regulatory Cells ◽  
Foam Cell ◽  
Regulatory Cells ◽  
T Helper ◽  
Antigen Specificity ◽  
Single Cell Rna Sequencing

The infiltration and accumulation of pro- and anti-inflammatory leukocytes within the intimal layer of the arterial wall is a hallmark of developing and progressing atherosclerosis. While traditionally perceived as macrophage- and foam cell-dominated disease, it is now established that atherosclerosis is a partial autoimmune disease that involves the recognition of peptides from ApoB (apolipoprotein B), the core protein of LDL (low-density lipoprotein) cholesterol particles, by CD4 + T-helper cells and autoantibodies against LDL and ApoB. Autoimmunity in the atherosclerotic plaque has long been understood as a pathogenic T-helper type-1 driven response with proinflammatory cytokine secretion. Recent developments in high-parametric cell immunophenotyping by mass cytometry, single-cell RNA-sequencing, and in tools exploring antigen-specificity have established the existence of several unforeseen layers of T cell diversity with mixed T H 1 and T regulatory cells transcriptional programs and unpredicted fates. These findings suggest that pathogenic ApoB-reactive T cells evolve from atheroprotective and immunosuppressive CD4 + T regulatory cells that lose their protective properties over time. Here, we discuss T cell heterogeneity in atherosclerosis with a focus on plasticity, antigen-specificity, exhaustion, maturation, tissue residency, and its potential use in clinical prediction.

scholarly journals Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2

2021 ◽  
Author(s):  
Patricia Kaaijk ◽  
Veronica Olivo Pimentel ◽  
Maarten E. Emmelot ◽  
Martien Poelen ◽  
Alper Cevirgel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Immune Memory ◽  
Effector Memory ◽  
Longitudinal Assessment ◽  
Memory T Cell ◽  
Cell Immunity

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. Methods: To determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19. Results: Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-ɣ T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-ɣ T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals. Conclusions: Our data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.

scholarly journals OMIC-11. SINGLE CELL RNA SEQUENCING FROM THE CSF OF SUBJECTS WITH H3K27M+ DIPG/DMG TREATED WITH GD2 CAR T-CELLULAR THERAPY

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i39-i39
Author(s):  
Aaron Mochizuki ◽  
Sneha Ramakrishna ◽  
Zina Good ◽  
Shabnum Patel ◽  
Harshini Chinnasamy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cell Product ◽  
Myeloid Suppressor Cells ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Single Cell Rna Sequencing

Abstract Introduction We are conducting a Phase I clinical trial utilizing chimeric antigen receptor (CAR) T-cells targeting GD2 (NCT04196413) for H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG). Cerebrospinal fluid (CSF) is collected for correlative studies at the time of routine intracranial pressure monitoring via Ommaya catheter. Here we present single cell RNA-sequencing results from the first 3 subjects. Methods Single cell RNA-sequencing was performed utilizing 10X Genomics on cells isolated from CSF at various time points before and after CAR T-cell administration and on the CAR T-cell product. Output was aligned with Cell Ranger and analyzed in R. Results As detailed in the Majzner et al. abstract presented at this meeting, three of four subjects treated at dose-level one exhibited clear radiographic and/or clinical benefit. We have to date completed single cell RNA-sequencing for three of these four subjects (two with benefit, one without). After filtering out low-quality signals and doublets, 89,604 cells across 3 subjects were analyzed. Of these, 4,122 cells represent cells isolated from CSF and 85,482 cells represent CAR T-cell product. Two subjects who demonstrated clear clinical and radiographic improvement exhibited fewer S100A8+S100A9+ myeloid suppressor-cells and CD25+FOXP3+ regulatory T-cells in the CSF pre-infusion compared to the subject who did not derive a therapeutic response. In one subject with DIPG who demonstrated improvement, polyclonal CAR T-cells detectable in CSF at Day +14 demonstrated enrichment of CD8A, GZMA, GNLY and PDCD1 compared to the pre-infusion CAR T-cells by trajectory analysis, suggesting differentiation toward a cytotoxic phenotype; the same subject exhibited increasing numbers of S100A8+S100A9+ myeloid cells and CX3CR1+P2RY12+ microglia over time. Further analyses will be presented as data become available. Conclusions The presence of immunosuppressive myeloid populations, detectable in CSF, may correlate to clinical response in CAR T cell therapy for DIPG/DMG.

scholarly journals Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8+ T cell repertoire upon viral exposure

2021 ◽  
Author(s):  
Joshua M. Francis ◽  
Del Leistritz-Edwards ◽  
Augustine Dunn ◽  
Christina Tarr ◽  
Jesse Lehman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Response ◽  
Hla Class I ◽  
T Cell Response ◽  
Class I ◽  
Epitope Specificity ◽  
Hla Genotype

AbstractEffective presentation of antigens by HLA class I molecules to CD8+ T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multi-omic technology to generate the first unified ex vivo characterization of the CD8+ T cell response to SARS-CoV-2 across 4 major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCR α/β sequence diversity, and the utilization of pre-existing SARS-CoV-2 reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations influence pre-existing immunity to SARS-CoV-2 and shape the immune repertoire upon subsequent viral exposure.One-Sentence SummaryWe perform a unified, multi-omic characterization of the CD8+ T cell response to SARS-CoV-2, revealing pre-existing immunity conditioned by HLA genotype.

scholarly journals The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

2021 ◽  
Author(s):  
Kevin Mohammed ◽  
Austin Meadows ◽  
Sandra Hatem ◽  
Viviana Simon ◽  
Anitha D Jayaprakash ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Influenza Vaccine ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cell Receptor ◽  
Physical Symptoms ◽  
T Cell Response ◽  
Tcr Repertoire

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

scholarly journals Re-investigation of classic T cell subsets and identification of novel cell subpopulations by single-cell RNA sequencing

2021 ◽  
Author(s):  
Xuefei Wang ◽  
Xiangru Shen ◽  
Shan Chen ◽  
Hongyi Liu ◽  
Ni Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Single Cell ◽  
Rna Sequencing ◽  
T Cell Activation ◽  
Expression Profiles ◽  
T Cell Subsets ◽  
Cell Subpopulation ◽  
Single Cell Rna Sequencing

AbstractClassic T cell subsets are defined by a small set of cell surface markers, while single cell RNA sequencing (scRNA-seq) clusters cells using genome-wide gene expression profiles. The relationship between scRNA-seq Clustered-Populations (scCPops) and cell surface marker-defined classic T cell subsets remain unclear. Here, we interrogated 6 bead-enriched T cell subsets with 62,235 single cell transcriptomes and re-grouped them into 9 scCPops. Bead-enriched CD4 Naïve and CD8 Naïve were mainly clustered into their scCPop counterparts, while cells from the other T cell subsets were assigned to multiple scCPops including mucosal-associated invariant T cells and natural killer T cells. The multiple T cell subsets that form a single scCPop exhibited similar expression pattern, but not vice versa, indicating scCPops are much homogeneous cell populations with similar cell states. Interestingly, we discovered and named IFNhi T, a new T cell subpopulation that highly expressed Interferon Signaling Associated Genes (ISAGs). We further enriched IFNhi T by FACS sorting of BST2 for scRNA-seq analyses. IFNhi T cluster disappeared on tSNE plot after removing ISAGs, while IFNhi T cluster showed up by tSNE analyses of ISAGs alone, indicating ISAGs are the major contributor of IFNhi T cluster. BST2+ T cells and BST2− T cells showing different efficiencies of T cell activation indicates high level of ISAGs may contribute to quick immune responses.

Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization

2019 ◽  
Vol 40 (48) ◽  
pp. 3924-3933 ◽  
Author(s):  
Ting-Ting Tang ◽  
Yi-Cheng Zhu ◽  
Nian-Guo Dong ◽  
Si Zhang ◽  
Jie Cai ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cell Receptor ◽  
T Cell Response ◽  
Phenotypic Characterization ◽  
Th1 Cells ◽  
Tcr Repertoire ◽  
Usage Patterns

Abstract Aims A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts. Methods and results Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ, granzyme B, and perforin. Conclusion We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.

scholarly journals Selective Cell State in the Clonally Expanded T-Cell Compartment of Vκ*MYC Mice Responding to Treatment with Checkpoint Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1581-1581
Author(s):  
Danielle C Croucher ◽  
Laura M Richards ◽  
Zhihua Li ◽  
Ellen nong Wei ◽  
Xian Fang Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Single Cell ◽  
Research Funding ◽  
Genetically Engineered ◽  
Cell State ◽  
Genetically Engineered Mouse Model ◽  
Tcr Repertoire

Abstract Introduction: Immune checkpoint receptor (ICR) blockade has emerged as an effective anti-tumour modality, but only in a subset of cancer patients. Moreover, in Multiple myeloma (MM), single-agent activity has not been observed, highlighting the need to better understand the mechanism of action of this class of drugs. We recently showed that combinatorial ICR blockade using αLAG3 and αPD-1 delays disease progression and improves survival in the transplantable Vκ*MYC model of MM (Croucher et al. ASH 2018). However, despite this being a controlled study with genetically-homogeneous tumours, anti-tumour immune responses were heterogeneous, with only a subset of mice demonstrating a delay in tumour progression (17/29 mice, response rate = 58.6%). Thus, using this model, we set out to define mechanisms underlying variability in response to ICR blockade. Methods: We established a cohort of mice by engrafting 5-week-old C57BL/6 mice with Vκ12598 cells via tail vein injection. Treatment with αLAG3/αPD-1 or Ig-control was initiated 1-week post-engraftment and bone marrow (BM) samples were collected 3 weeks after the start of treatment. Following FACS-enrichment of T cells and plasma cells (PCs), single cell suspensions were subjected to matched single-cell gene expression (5' scRNA-seq) and T cell receptor (TCR)/B cell receptor (BCR) profiling (10x Genomics). Results: Samples were selected for profiling based on response to treatment, with responders (n=4) defined by significantly lower disease burden compared to non-responders (n=3) and control-treated mice (n=5), as measured by serum M-protein and %PCs in BM/spleen at sacrifice. Unsupervised clustering of scRNA-seq data from PCs (n=3,318 cells) identified no gene expression or BCR repertoire differences between control and treated, or between responder and non-responder samples, supporting that variability in response was not related to malignant Vκ12598 cells themselves. Across all samples, a statistically significant difference was not detected between the total number of unique TCR sequences (clonotypes) comparing control-treated (351-2369), non-responders (1185-2327) and responders (1378-1698), with no overlapping TCR sequences between top clonotypes. Evaluation of TCR repertoire diversity revealed that αLAG3/αPD-1 treatment induces clonal T cell expansion in control versus treated mice, but this was not significantly different between responders and non-responders. Analysis of paired scRNA-seq data (n=21,520 cells) revealed that expanded T cells from αLAG3/αPD-1-treated mice occupy a different cell state in responder vs. non-responder mice. We speculate that underlying differences in the TCR repertoire may dictate the downstream phenotype of expanded, anti-tumour T cells in mice treated with combinatorial αLAG3/αPD-1. Tumour control following treatment was associated with clonal expansion of T cells expressing genes related to cytoxicity and activation (Ccl5, Ifng, Fasl, Gzmb), whereas tumour progression was associated with clonal expansion of proliferative T cells (Cdkn3, Birc5, Ccna2, Aurka, Mki67). Although T cell proliferation is typically a phenotype ascribed to effector T cells, recent studies have similarly observed this proliferative cell state in dysfunctional T cells within melanoma tumours. Moreover, emerging evidence supports suppression of T cell proliferation by CDK4/6 inhibitors as a means to augment anti-tumour activity of ICR-based therapy. Thus, studies exploring whether reversal of the observed proliferative T cell state can restore response to αLAG3/αPD-1 treatment in non-responding Vκ12598 mice are ongoing and will be reported. Conclusions: ICR inhibitors demonstrate significant activity in some cancers, however many patients fail to respond and a similarly promising level of efficacy has not been achieved in MM. Studies aimed at unraveling the mechanisms of response and resistance to ICR inhibitors are therefore needed to improve the utility of this class of drugs for all patients. Our approach of using paired single-cell gene expression and TCR repertoire profiling has enabled identification of molecular cell states specifically in expanded T cells of responder vs. non-responder mice. In turn, our work nominates novel mechanisms that may be used as potential biomarkers for anti-tumour immune responses as well as potential targets to augment responses to ICR blockade therapy. Disclosures Chesi: Abcuro: Patents & Royalties: Genetically engineered mouse model of myeloma; Novartis: Consultancy, Patents & Royalties: human CRBN transgenic mouse; Pfizer: Consultancy; Pi Therapeutics: Patents & Royalties: Genetically engineered mouse model of myeloma; Palleon Pharmaceuticals: Patents & Royalties: Genetically engineered mouse model of myeloma. Bergsagel: GSK: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sebag: Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria. Trudel: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; Genentech: Research Funding.

scholarly journals Induction of a virus-specific effector–memory CD4+ T cell response by attenuated SIV infection

2006 ◽  
Vol 203 (12) ◽  
pp. 2661-2672 ◽  
Author(s):  
Marie-Claire Gauduin ◽  
Yi Yu ◽  
Amy Barabasz ◽  
Angela Carville ◽  
Mike Piatak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
High Frequency ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Specific Effector

We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVΔnef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4–10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5–10-fold lower in frequency and inversely correlated with the level of plasma viremia. SIV-specific CD4+ cells from SIVΔnef animals were predominantly CD27−CD28−CD45RAlowCCR7−CCR5−, consistent with an effector–memory subset, and included a fully differentiated CD45RA+CCR7− subpopulation. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD27+CD28+CD45RA−CCR7+CCR5+, consistent with an early central memory phenotype. The CD45RA+CCR7−CD4+ subset from SIVΔnef animals was highly enriched for effector CD4+ T cells, as indicated by the perforin expression and up-regulation of the lysosomal membrane protein CD107a after SIV Gag stimulation. SIV-specific CD4+ T cells in attenuated SIV-infected animals were increased in frequency in bronchioalveolar lavage and decreased in lymph nodes, consistent with an effector–memory T cell population. The ability of SIVΔnef to induce a high frequency virus-specific CD4+ T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.

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