Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Abstract Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2–mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4+ Tregs to CD8+CD25+ effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell–stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment.

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Janus Kinase-2 Inhibition Induces Durable Tolerance to Alloantigen by Dendritic Cell-Stimulated Human T Cells, Yet Preserves Immunity to Recall Antigen

Blood ◽

10.1182/blood.v118.21.1903.1903 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1903-1903

Author(s):

Brian C. Betts ◽

Omar Abdel-Wahab ◽

Shane A Curran ◽

Erin T St. Angelo ◽

Priya Koppikar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Th17 Cells ◽

Janus Kinase ◽

Effector Memory ◽

Solid Organ ◽

Janus Kinase 2 ◽

Jak2 Inhibitor ◽

Human T Cells ◽

Jak2 Inhibition

Abstract Abstract 1903 Janus kinase 2 (JAK2) conveys signals from receptor binding by several inflammatory cytokines, including IL-6, IL-12, and IL-23, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). These cytokines promote the development and expansion of T helper 1 (Th1) cells, which use IL-12, and Th17 cells, which use IL-6 and IL-23. Th1 and Th17 cells can in turn induce alloreactive end organ damage in GvHD. JAK2 is therefore a principle gatekeeper of alloreactivity and inflammation, and it represents an attractive target to control GvHD. We demonstrate that TG101348, a synthetic small molecule, highly selective JAK2 inhibitor, when present during initial and secondary encounters between human T cells and allogeneic monocyte-derived dendritic cells (moDCs), induces durable, profound, and specific T cell tolerance on reexposure to the same alloantigens. TG101348 ablates IL-6/JAK2-mediated phosphorylation of STAT3 in T cells (24% v 0%, P<0.05, n=5) but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which would interfere with Tregs and other effector T cell responses. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4+ Tregs to CD8+CD25+ effector T cells in favor of Tregs (Treg:Effector 1:2 vs 1:1, P<0.05, n=5). JAK2 inhibition also reduces the production of IL-6 (255 vs 157 pg/ml, P<0.05, n=5) and TNF-alpha (50 vs 15 pg/ml, P<0.05, n=4) in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 (24% vs 14%, P<0.05, n=4) and Th17 (2% vs 1%, P<0.05, n=4). T cells, stimulated by moDCs in the presence of TG101348, demonstrate a marked reduction in proliferative capacity upon reexposure to fresh allogeneic moDCs from the original stimulating party, even in the absence of the JAK2 inhibitor during the secondary MLR (P<0.05, n=4). Responses to stimulation de novo by influenza matrix peptide (fluMP), a pathogenic nominal antigen, remain intact (P=NS, n=4). Conversely, TG101348 also inhibits secondary MLR responses by T cells, which have already been sensitized to alloantigens in a primary MLR without the JAK2 inhibitor (P<0.05, n=4). The durable tolerance against full HLA disparities in each of these settings provides preclinical data in vitro that JAK2 represents a relevant biologic target for preventing or treating graft-versus-host disease (GvHD), or even solid organ allograft rejection, without broader immune impairment. Disclosures: No relevant conflicts of interest to declare.

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Establishing CD8+ T Cell Immunity by Adoptive Transfer of Autologous, IL-15 Expanded, Anti-Tumor CTL with a Central/Effector Memory Phenotype Can Induce Objective Clinical Responses.

Blood ◽

10.1182/blood.v114.22.782.782 ◽

2009 ◽

Vol 114 (22) ◽

pp. 782-782 ◽

Cited By ~ 1

Author(s):

Marcus Butler ◽

Philip Friedlander ◽

Mary Mooney ◽

Linda Drury ◽

Martha Metzler ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Adoptive Transfer ◽

De Novo ◽

Effector Memory ◽

Large Numbers ◽

Central Effector

Abstract Abstract 782 The goal of cellular immunotherapy is to build long-lasting anti-tumor immunologic “memory” in patients and reject tumors for a lifetime. Previously, we and others demonstrated that IL-15 promotes the generation of T cells with a central memory (CM) phenotype which have the capacity to persist and establish effective anti-tumor memory in vivo. Furthermore, it has been shown that CD83 delivers a CD80-dependent T cell stimulatory signal that allows T cells to be long-lived. Based on these findings, we developed a system to generate large numbers of long-lived antigen-specific CD8+ T cells with a memory phenotype. This in vitro culture system utilizes IL-15 and a standardized, renewable artificial antigen presenting cell (aAPC) which was produced by transducing CD80, CD83, and HLA-A*0201 to the human cell line, K562. This aAPC can uniquely support the priming and prolonged expansion of large numbers of antigen-specific CD8+ CTL which display a central/effector memory (CM/EM) phenotype, possess potent effector function, and can be maintained in vitro for >1 year without any feeder cells or cloning. We hypothesized that adoptive transfer of these CTL with a CM/EM phenotype should result in anti-tumor memory in humans even without lymphodepletion or high dose IL-2. For our “first-in-human” clinical study, we chose the melanoma antigen MART1 as a target antigen, since MART1-specific HLA-A*0201+-restricted precursor CTL are detectable in some melanoma patients and can be immunophenotyped pre-infusion. Autologous CD8+ T cells were stimulated weekly with peptide-pulsed human cell-based aAPC and expanded with low dose IL-2 and IL-15. After three weeks, polyclonal MART1 CTL were reinfused without additional lymphodepletion, chemotherapy, IL-2, or vaccination. Eight study participants have enrolled and received a total of 15 MART1 CTL infusions (31% MART1 multimer positivity, median). All but one subject received two reinfusions where the 2nd graft was produced from CD8+ T cells harvested two weeks after the 1st reinfusion. To date, ≥2×109 CTL with potent effector function and a CM/EM phenotype were successfully generated for all subjects. No dose limiting toxicities were observed at either Dose Level 1 (2×108/m2) or Dose Level 2 (2×109/m2). Clinical activity was observed with a response by RECIST criteria in 1 subject, which was confirmed by a negative PET/CT 100 days following the last CTL infusion. In addition, 1 patient experienced a mixed response, 1 had stable disease, 3 had progression, and 2 are currently on active therapy. Multimer staining showed that, immediately post infusion, the percentage of CD8+ T cells specific for MART1 temporarily increased in all subjects, with the highest (6.5%) observed in subject #7. In 4 subjects, sustained increases in the frequency of MART1 specific T cells by more than two-fold (range 2.0-10x) for ≥21 days were observed despite the fact that no exogenous cytokines or vaccination was administered. Moreover, an increase of detectable MART1 specific T cells which display a CM phenotype was observed in all evaluable subjects and was observed for ≥35 days in 6 of 8 subjects. In subject #2, the conversion of MART1 CTL immunophenotype from a naïve to a mixture of naïve/memory phenotypes was observed for more than 6 months. We identified 10 individual MART1 T cell clonotypes from peripheral CD45RA- memory T cells on day 21. Clonotypic TCR Vbeta CDR3 analysis revealed that CTL grafts contained 7 out of 10 of these clonotypes. Furthermore, 6 clonotypes persisted in the peripheral CD45RA- memory fraction on days 39, 67 and/or 132. In Subject #3, who showed a mixed clinical response, 5 individual MART1 T cell clonotypes were isolated from lung metastases. 4 out of 5 clones were included in the CTL grafts. This finding supports the possibility that infused CTL can traffic and localize to sites of disease. Intriguingly, in both subjects, we were able to identify MART1 CTL clonotypes that were not detectable in the CTL grafts but possibly emerged after CTL infusion, indicating that adoptive transfer of MART1-specific CTL may provoke a de novo antitumor response. Taken together, these results suggest that CM/EM MART1 CTL generated ex vivo using our cell-based artificial APC in the presence of IL-15 may persist in vivo and induce de novo anti-tumor responses. Further enhancement of anti-tumor activity may be achieved through vaccination, cytokine administration, and/or removal of cytokine sinks and inhibitory factors following appropriate lymphodepletion. Disclosures: No relevant conflicts of interest to declare.

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Dendritic cell–activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity

Blood ◽

10.1182/blood-2003-09-3135 ◽

2004 ◽

Vol 103 (10) ◽

pp. 3970-3978 ◽

Cited By ~ 76

Author(s):

Yi Zhang ◽

Gerard Joe ◽

Jiang Zhu ◽

Richard Carroll ◽

Bruce Levine ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

Graft Versus Host Disease ◽

T Cell Subsets ◽

Effector Memory ◽

Antitumor Effects ◽

Host Disease ◽

Graft Versus Host

Abstract Graft versus host disease (GVHD) is triggered by host antigen-presenting cells (APCs) that activate donor T cells to proliferate and differentiate, but which APC-activated donor T-cell subsets mediate GVHD versus beneficial antitumor effects is not known. Using a CD8+ T cell–dependent mouse model of human GVHD, we found that host dendritic cell (DC)–induced CD44hiCD8+ effector/memory T cells were functionally defective in inducing GVHD, whereas CD44loCD8+ naive phenotype T cells were extremely potent GVHD inducers. Depletion of CD44loCD8+ T cells from host DC-stimulated T cells before transplantation prevented GVHD without impairing their antitumor activity in vivo. Compared with CD44loCD8+ T cells, CD44hiCD8+ T cells expressed high levels of Fas and were efficiently deleted in vivo following transplantation. These results suggest that ex vivo allogeneic DC stimulation of donor CD8+ T cells may be useful for the prevention of GVHD and for optimizing antitumor therapies in vivo.

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CD28 Fails to Costimulate Tumor-Specific Activation of Epstein Barr-Virus-Specific Memory Effector T Cells.

Blood ◽

10.1182/blood.v106.11.1294.1294 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1294-1294

Author(s):

Bianca Altvater ◽

Sibylle Pscherer ◽

Heribert Juergens ◽

Claudia Rossig

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Surface Expression ◽

Effector T Cells ◽

Effector Memory ◽

Cytotoxic T Cell ◽

Barr Virus ◽

Epstein Barr ◽

Signaling Domains

Abstract Genetic modification of cytotoxic T cells with tumor antigen-specific chimeric receptors (chRec) specifically redirects their effector functions towards tumor cells. Integration of the signaling domains of the costimulatory molecule CD28 into chRec enhances antigen-specific proliferation of peripheral blood-derived polyclonal human T cell populations. While CD28 plays an essential role in the priming of naïve CD4+ T cells, its contribution to effector memory cytotoxic T cell (CTL) responses is controversial. We investigated the function of chRec containing the signaling domains of CD28 in vitro expanded T cells with specificity for Epstein-Barr-virus (EBV). Chimeric T cell receptors containing an extracellular single-chain antibody domain directed against the tumor ganglioside antigen GD2 fused to the intracellular signaling domains of both the CD28 and the T cell receptor (TCR) ζ chain (14.G2a-CD28ζ), or TCRζ alone (14.G2a-ζ) were expressed in EBV-specific cytotoxic T cell (CTL) lines from three seropositive donors and in peripheral blood T cells preactivated by CD3-/CD28-specific antibody crosslinking by retroviral gene transfer. Following transduction with the chRec genes, 14.G2a-ζ and 14.G2a-CD28ζ EBV-CTL had comparable levels of chRec surface expression (21–28% versus 26–40%). EBV-CTL had an immunophenotype characteristic of memory effector T cells, coexpressing CD3 and CD45RO in the absence of CD45RA and CD27 surface expression. The transduced CTL maintained their capacity to specifically lyse autologous EBV targets in 4 hr 51Cr release assays and to proliferate after stimulation with autologous EBV targets. Intracellular cytokine staining demonstrated efficient and comparable antigen-specific IFN-γ secretion by both 14.G2a-ζ and 14.G2a-CD28ζ-transduced CTL in response to EBV and tumor targets. Furthermore, GD2+ neuroblastoma targets were lysed in a comparable and antigen-specific manner. However, while antigen engagement by 14.G2a-CD28ζ efficiently induced expansion of non-specifically activated polyclonal peripheral blood lymphocytes in an antigen-dependent manner, CD28 signaling failed to overcome the failure of transduced EBV-CTL to specifically proliferate in response to GD2+ tumor cells. Thus, the costimulatory requirement for the highly efficient proliferative activation response of EBV-specific CTL to viral antigen can not be mimicked by combined CD28 and ζ signaling. Exploring the mechanisms and costimulatory requirements of effector memory T cell reactivation may help to exploit the full potential of this highly cytolytic T cell population for adoptive immunotherapy of cancer.

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Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Blood ◽

10.1182/blood-2010-10-310599 ◽

2011 ◽

Vol 117 (6) ◽

pp. 1888-1898 ◽

Cited By ~ 115

Author(s):

Xiuli Wang ◽

Carolina Berger ◽

ChingLam W. Wong ◽

Stephen J. Forman ◽

Stanley R. Riddell ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Effector T Cells ◽

Central Memory ◽

Model Systems ◽

Adoptive T Cell Therapy ◽

Effector Memory ◽

T Cell Therapy ◽

Effector Cells

Abstract In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (TE) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8+ TE cells derived from purified CD45RO+CD62L+ central memory (TCM) or CD45RO+CD62L− effector memory (TEM) precursors in an immunodeficient mouse model. The engraftment of TCM-derived effector cells (TCM/E) was dependent on human interleukin-15, and superior in magnitude and duration to TEM-derived effector cells (TEM/E). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8+ TCM/E engraftment was polyclonal, suggesting that the ability to engraft is a general feature of TCM/E. CD8+ TEM/E proliferated extensively after transfer but underwent rapid apoptosis. In contrast, TCM/E were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8+ effector T cells derived from TCM precursors may be preferred for adoptive therapy based on superior engraftment fitness.

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Effector T-cells are expanded in systemic lupus erythematosus patients with high disease activity and damage indexes

Lupus ◽

10.1177/0961203317722848 ◽

2017 ◽

Vol 27 (1) ◽

pp. 143-149 ◽

Cited By ~ 10

Author(s):

S Piantoni ◽

F Regola ◽

A Zanola ◽

L Andreoli ◽

F Dall’Ara ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Damage Index ◽

Effector T Cells ◽

Cd4 T Cell ◽

Effector Memory ◽

Healthy Controls ◽

Systemic Lupus

Background and objectives T-cell activation may be one of the pathogenic mechanisms of systemic lupus erythematosus (SLE). After repeated antigenic stimulation, T-cells undergo different modifications, leading to the differentiation into effector memory T-cells (CCR7−CD45RA−) and terminally differentiated effector memory (TDEM) T-cells (CCR7−CD45RA+). Similarly, down-modulation of CD28 may lead to the expansion of the CD28− T-cells, a subpopulation with peculiar effector activities. The aim of this study was the characterization of T-cell phenotype in a cohort of patients with SLE according to disease activity and damage index. Materials and methods Phenotypic analysis of peripheral blood T lymphocytes of 51 SLE patients and 21 healthy controls was done by flow-cytometry. SLE disease activity was evaluated by SLE Disease Activity Index-2000 (SLEDAI-2K) and damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The variations between different groups were evaluated by Mann–Whitney test. Bonferroni correction was applied to adjust for multiple comparisons ( padj). Spearman rank test was used to evaluate the correlations between quantitative variables. Results CD4+ lymphopenia was found among SLE patients. Patients showed a trend for a higher percentage of TDEM among the CD4+ T-cell subpopulation in comparison with healthy controls ( p = .04). SLE patients were divided into two groups according to disease activity: patients with SLEDAI-2K ≥ 6 ( n = 13) had a higher percentage of circulating CD4+ T-cells with CD28− phenotype ( padj = .005) as well as those with an effector memory ( padj = .004) and TDEM ( padj = .002) phenotype and a trend of decrease of regulatory T-cells (TREGs) ( p = .02), in comparison with patients with low disease activity ( n = 38). Patients with damage (SDI ≥ 1) tended to show an expansion of TDEM among CD4+ T-cells as compared with patients with no damage ( p = .01). In SLE patients an inverse correlation was found between the percentages of TREGs and those of TDEM ( p < .01) or CD4 + CD28− ( p < .01) T-cells. Conclusions CD4+ T-cell subpopulations displaying phenotype characteristics of effector lymphocytes are proportionally expanded in patients with active SLE and a higher damage index. These findings may suggest a role of effector T-cells in the pathogenesis of the disease and in the mechanisms of damage in SLE.

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Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Mucosal Immunology ◽

10.1038/s41385-021-00423-5 ◽

2021 ◽

Author(s):

Maria E. Joosse ◽

Fabienne Charbit-Henrion ◽

Remy Boisgard ◽

Rolien C. Raatgeep ◽

Dicky J. Lindenbergh-Kortleve ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Early Onset ◽

Intestinal Inflammation ◽

De Novo ◽

Cell Receptor ◽

Effector Memory ◽

Colonic Disease ◽

Cd25 Expression

AbstractSingle genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

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Expansion of effector and memory T cells is associated with increased survival in recurrent glioblastomas treated with dendritic cell immunotherapy

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz022 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 2

Author(s):

Marica Eoli ◽

Cristina Corbetta ◽

Elena Anghileri ◽

Natalia Di Ianni ◽

Micaela Milani ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

T Cell Activation ◽

Cell Activation ◽

Memory T Cells ◽

Therapeutic Modality ◽

Effector Memory ◽

Autologous Tumor ◽

Vaccine Site

Abstract Background The efficacy of dendritic cell (DC) immunotherapy as a single therapeutic modality for the treatment of glioblastoma (GBM) patients remains limited. In this study, we evaluated in patients with GBM recurrence the immune-mediated effects of DC loaded with autologous tumor lysate combined with temozolomide (TMZ) or tetanus toxoid (TT). Methods In the phase I-II clinical study DENDR2, 12 patients were treated with 5 DC vaccinations combined with dose-dense TMZ. Subsequently, in eight patients, here defined as Variant (V)-DENDR2, the vaccine site was preconditioned with TT 24 hours before DC vaccination and TMZ was avoided. As a survival endpoint for these studies, we considered overall survival 9 months (OS9) after second surgery. Patients were analyzed for the generation of effector, memory, and T helper immune response. Results Four of 12 DENDR2 patients reached OS9, but all failed to show an immunological response. Five of eight V-DENDR2 patients (62%) reached OS9, and one patient is still alive (OS >30 months). A robust CD8+ T-cell activation and memory T-cell formation were observed in V-DENDR2 OS>9. Only in these patients, the vaccine-specific CD4+ T-cell activation (CD38+/HLA-DR+) was paralleled by an increase in TT-induced CD4+/CD38low/CD127high memory T cells. Only V-DENDR2 patients showed the formation of a nodule at the DC injection site infiltrated by CCL3-expressing CD4+ T cells. Conclusions TT preconditioning of the vaccine site and lack of TMZ could contribute to the efficacy of DC immunotherapy by inducing an effector response, memory, and helper T-cell generation.

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Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of oxygen reactive species

10.1101/2020.03.06.978791 ◽

2020 ◽

Cited By ~ 2

Author(s):

Anouk Lepez ◽

Tiphène Pirnay ◽

Sébastien Denanglaire ◽

David Perez-Morga ◽

Marjorie Vermeersch ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Effector T Cells ◽

Effector Memory ◽

T Cell Proliferation ◽

Metabolic Enzyme ◽

Ros Production

AbstractThe AMP-activated kinase (AMPK) is a major energy sensor metabolic enzyme that is activated early during T cell immune responses but its role in the generation of effector T cells is still controversial.Using both in vitro and in vivo models of T cell proliferation, we show herein that AMPK is dispensable for early TCR signaling and short-term proliferation but required for sustained long-term T cell proliferation and effector / memory T cell survival. In particular, AMPK promoted accumulation of effector / memory T cells in competitive homeostatic proliferation settings. Transplantation of AMPK-deficient hematopoïetic cells into allogeneic host recipients led to a reduced graft-versus-host disease, further bolstering a role for AMPK in the expansion and pathogenicity of effector T cells.Mechanistically, AMPK expression enhances the mitochondrial membrane potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Moreover, dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of T cell fitness.

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CMV Status Drives Distinct Trajectories of CD4+ T Cell Differentiation

Frontiers in Immunology ◽

10.3389/fimmu.2021.620386 ◽

2021 ◽

Vol 12 ◽

Author(s):

Weiwen Zhang ◽

Anna B. Morris ◽

Erica V. Peek ◽

Geeta Karadkhele ◽

Jennifer M. Robertson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

De Novo ◽

Memory T Cells ◽

Gene Set Enrichment Analysis ◽

Careful Examination ◽

Effector Memory ◽

Effector Memory T Cells ◽

Cytotoxic Function

Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual’s immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to de novo infections, vaccines, cancers, or rejection. Therefore, careful examination of T cell responses elicited by CMV is warranted to understand their potentially beneficial or harmful roles in future major immune events. Our detailed exploration of the distribution, phenotype, TCR repertoire and transcriptome of CD4+ T cells within CMV seropositive healthy individuals using high-dimensional flow cytometry and single cell multi-omics sequencing reveals that CMV seropositivity has highly significant age-independent effects, leading to a reduction in CD4+ naïve T cells and an expansion of CD4+ effector memory T cells and CD45RA+ effector memory T cells. These induced CD4+ effector memory T cells undergo a specific differentiation trajectory resulting in a subpopulation of CD57+CD27-CD28-CD244+ CD4+ T cells with cytotoxic function and TCR oligoclonality for optimal controlled coexistence with cytomegalovirus. Through gene set enrichment analysis, we found that this subpopulation is similar to virus-specific CD8+ T cells and T cells that mediate acute rejection in patients using tacrolimus and belatacept, a selective costimulation blocker. Together, these data suggest that memory CD4+ T cells induced by cytomegalovirus are formed via a distinct differentiation program to acquire cytotoxic function and can be potentially detrimental to transplant patients adopting costimulation blockade immunosuppressive regimen.

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