DR3 Signaling Modulates the Function of Foxp3+ regulatory T Cells and the Severity of Acute Graft and Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2148-2148
Author(s):  
Hidekazu Nishikii ◽  
Kim Byung-Su ◽  
Yan Chen ◽  
Jeanette Baker ◽  
Antonio Pierini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Host Disease ◽  
Transplantation Experiments ◽  
Acute Graft

Abstract Background : CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft versus host disease (GVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). We recently demonstrated that a single treatment of the agonistic antibody to DR3 (Death receptor 3, aDR3) to donor mice resulted in the expansion/activation of donor derived Treg and prevented acute GVHD (Blood 126:546, 2015), although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we investigated the efficacy of αDR3 treatment to recipient mice in model of murine GVHD. Methods To analyze the DR3 expression in immune cells with or without TCR stimulation, we comprehensively analyzed the cells with multicolor cytometry using viSNE (visualization of stochastic neighbor embedding algorithm). In transplantation experiments, 5x10e6 T cell depleted bone marrow (from WT C57BL/6 mice, H2kb) and 1x10e6 T cells (C57BL/6-Luciferase mice, H2kb) were injected intravenously into lethally irradiated (8Gy in total) BALB/c recipient mice (H2kd). aDR3 was intraperitonealy injected at different time point after transplantation. The transplanted mice were monitored by clinical GVHD score, weight, bioluminescence imaging (BLI) for donor T cell trafficking, and survival time. To investigate the role of donor or recipient derived Treg in this model, in vivo Treg depletion using B6-Foxp3DTR mice was also performed. Results viSNE analysis demonstrated that DR3 was preferentially expressed on resting-Treg (79%), although a subpopulation of CD4+Foxp3-T cells (59%), CD8+T cells (24%), and NK1.1+TCRb+NKT celsl (42%) also expressed DR3. However, DR3 expressions in CD4+Foxp3-T cells and CD8+T cells were elevated after TCR stimulation in vitro (p<0.01). These data suggested that activation of DR3 signaling would also affect the function of conventional T cell upon activation. In the mixed lymphocyte reaction using allogeneic T cells (from WT C57BL/6 mice) and irradiated splenocytes (from BALB/c mice), the activation of DR3 promoted allogeneic T cell proliferation (p<0.01). In transplantation experiments, aDR3 treatment (day 3 after transplant) to animals with ongoing GVHD failed to expand Treg and further promoted donor T cell activation/proliferation with worse outcomes (p<0.05 in BLI study, p<0.01 in survival). However, the prophylactic treatment of animals with aDR3 (day 0 αDR3 and day 2 allogeneic T cells) resulted in the expansion of recipient derived Treg (H2kd+CD4+Foxp3+ cells, p<0.01) and reduced the severity of GVHD with markedly prolonged survival (p<0.001). These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. This survival benefit could be observed even if Treg were depleted from the donor allogeneic T cells (from diphtheria toxin treated B6-Foxp3DTR mice), suggesting that host derived Treg, rather than donor cells, play a critical role in abrogating GVHD in this model. Conclusion In conclusion, we demonstrated that activation through DR3 signaling not only expands and activates Treg, but also further activates conventional alloreactive T cells and has very different clinical impact depending upon the timing of administration. These data provide important information for future clinical translation using modification of DR3 signaling. Disclosures Negrin: Stanford University: Patents & Royalties.

scholarly journals CD8+ T Cells in Atherosclerosis

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 37
Author(s):  
Sarah Schäfer ◽  
Alma Zernecke
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Immune Checkpoints ◽  
Cell Functions

Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8+ T cells ameliorates atherosclerosis. CD8+ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8+ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8+ T cells and their cytotoxic activity. CD8+ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8+ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8+ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8+ T cells in atherosclerosis.

scholarly journals Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

2021 ◽  
Vol 118 (23) ◽  
pp. e2103730118
Author(s):  
Yuka Nakajima ◽  
Kenji Chamoto ◽  
Takuma Oura ◽  
Tasuku Honjo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Effector Memory ◽  
T Cell Subset ◽  
Aged Mice ◽  
Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

scholarly journals Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3300-3307 ◽  
Author(s):  
Christian A. Wysocki ◽  
Qi Jiang ◽  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Karen P. McKinnon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Allogeneic Bone Marrow Transplantation ◽  
Lymphoid Tissues ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

AbstractCD4+CD25+ regulatory T cells (Tregs) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by Tregs expressing the lymphoid homing molecule l-selectin. Here, we demonstrate that Tregs lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5-/- Tregs was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) Tregs. CCR5-/- Tregs were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of Tregs within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5-/- Tregs correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in Treg function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of Tregs to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation.

Expanded CD4+Foxp3+ Regulatory T Cells through DR3 Signaling Have a Distinct Immunophenotype and Abrogate the Lethal Acute-Graft and Host Disease after Allogeneic Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1876-1876
Author(s):  
Hidekazu Nishikii ◽  
Byung-Su Kim ◽  
Yasuhisa Yokoyama ◽  
Jeanette Baker ◽  
Antonio Pierini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Proliferation ◽  
Agonistic Antibody ◽  
Host Disease ◽  
Acute Graft

Abstract Background : CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells which regulate the immune system, maintain self-tolerance and enhance immune tolerance after transplantation. Several groups have demonstrated that donor-derived Treg prevent the development of lethal acute graft and host disease (GVHD) in murine allogeneic transplant models. However, the low frequency of Treg limits clinical translation. To overcome the paucity of Treg, several strategies have been developed for Treg expansion. However, the activation of other immune cells and the instability of Foxp3 expression in ex vivo culture are problematic for widescale clinical usage. Recently, we showed that a single dose of agonistic antibody to DR3 (Death receptor 3, also called tumor necrosis factor super family 25; TNFSF25) into donor mice resulted in the expansion of donor derived Treg and prevented acute GVHD (Blood. 2015). Although the treatment with DR3 antibodies can preferentially expand Treg in vivo, the precise role of DR3 signaling in Treg has not been fully elucidated. In this study, we investigated the immune phenotype, gene expression profiles, and function of Treg after activation with DR3 signaling. Methods: To analyze the heterogeneous immunophenotype of Treg after DR3 signal activation, we comprehensively analyzed multicolor cytometry data using viSNE (visualization of stochastic neighbor embedding algorithm). For gene expression analysis using microarray (Affymetrix GeneChip 2.0 ST Array), CD4+Foxp3+ cells from Foxp3-GFP mice with or without DR3 activation were sorted by FACS. Normalized expression data was analyzed using TIGR Multi Experiment Viewer (MeV, version 4.9). To investigate the function of Treg after DR3 activation, CD4+CD25+Treg from wild type (WT) C57BL/6 mice (H2kb) with or without treatment of agonistic antibody to DR3 were isolated by FACS and then injected into lethally irradiated (8Gy in total) BALB/c mice (H2kd) together with 5x106 T cell depleted bone marrow (from WT C57BL/6 mice) and 1x106 T cells (C57BL/6-luciferase mice). The transplanted mice were monitored by clinical GVHD score, weight, bioluminescence imaging (BLI) for donor T cell trafficking and survival. Results: The results of viSNE showed the heterogenic elevated expression level of Nrp1, Helios (natural occurring Treg marker/transcription factor), CD103, KLRG1, CD44, ICOS, PD-1, Lag3, TIGIT (effector or inhibitory molecules), and Ki67 (proliferation marker) in Treg after DR3 activation. On the other hand, the expression of CD25, the receptor for IL-2 was down regulated. In the microarray data, a significant elevated level (>2 fold relative expression levels in DR3 activated Treg) of chemokine/cytokine (ccr3, cxcl10) and effector molecules (CD74, Gzmb) were observed. These data suggest that the effect of DR3 signaling in Treg results in not only the expansion of Treg but also their activation. In transplantation experiments, the mice that received DR3 activated Treg (5X105/mouse) showed significantly lower donor T cell proliferation compared with the mice that received non-activated Tregs (n=5 in each group, P<0.01 on day 7 and 10 after transplant). Interestingly, even a smaller number (1x105/mouse) of DR3 treated Treg suppressed donor T cell proliferation in host mice (n=5 in each group, P<0.05 on day7 and day10), and the survival of the mice in the DR3 activated Treg group was also improved compared with control GVHD group (n=10 in each group, P<0.01 in Log-rank test). These data suggested that Treg isolated after DR3 activation were more functional for the prevention in GVHD. Conclusion: In conclusion, our data demonstrate that the activation of DR3 signaling can induce Treg populations with enhanced function in vivo. These observations support for future clinical testing using human DR3 signal modulation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Critical role of host γδ T cells in experimental acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 749-755 ◽  
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Kathleen P. Lowler ◽  
Chen Liu ◽  
Dennis Keith Bishop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Γδ T Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α

Abstract γδ T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host γδ T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host γδ T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) γδ monoclonal antibody reduced GVHD, and γδ T-cell-deficient (γδ-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P &lt; .001). γδ T cells were responsible for this difference because reconstitution of γδ-/- recipients with γδ T cells restored GVHD mortality. γδ-/- recipients showed decreased serum levels of tumor necrosis factor α (TNF-α), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from γδ-/- recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with γδ T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon γ (IFN-γ), TNF-α, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host γδ T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells. (Blood. 2005;106:749-755)

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

T Cell Activation and Regulation in Graft-Versus-Host Disease: Integral Role of CD28, CTLA4 and GITR Splice Variants.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3054-3054
Author(s):  
Yuji Miura ◽  
Christopher J. Thoburn ◽  
Emilie C. Bright ◽  
Elizabeth C. Matsui ◽  
William H. Matsui ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Splice Variants ◽  
Treg Cells ◽  
Mrna Splice ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a serious, life-threatening complication that occurs following allogeneic (allo) bone marrow transplantation (BMT). The use of non-specific immunosuppression or T cell depletion has reduced the incidence of GVHD but at the expense of increased rates of infection and leukemic relapse. Modulation of the major costimulatory pathway (CD28/CTLA4:B7) involved in T cell activation and regulation may lead to specific immune tolerance in the absence of global non-specific immunosuppression. The identification of mRNA splice variants encoding for soluble forms of CD28, CTLA4 and GITR suggests that costimulation of T cells is complex and is not limited to cell-cell contact. The present studies examined the hypothesis that the onset of GVHD and the re-establishment of immune tolerance correlate with the expression levels of these costimulatory molecules. mRNA transcript levels for the soluble (s) and full-length (fl; cell surface associated) variants assessed by quantitative PCR, were temporally examined in peripheral blood lymphocytes (PBLs) from patients undergoing alloBMT (n=38) or autologous (auto) BMT (n=39) with the induction of autoGVHD by cyclosporin A treatment post-transplant. Levels of s and fl CD28 mRNA transcripts in PBLs were significantly increased (&gt;1.5 fold, P&lt;0.05) in patients developing either allo or autoGVHD compared to patients who do not develop GVHD. s and flCTLA4 levels in patients at the onset of allo and autoGVHD were significantly decreased compared to healthy controls (n=22) (&gt;2.3-fold, P&lt;0.01). s and flCTLA4 expression in patients with autoGVHD was significantly decreased compared to patients without autoGVHD (&gt;2.1-fold). sCTLA4 expression in patients with alloGVHD was significantly decreased than patients without alloGVHD. Interestingly, temporal analysis revealed that the levels for sCTLA4 paralleled the recovery from GVHD implicating an active process in the establishment of non-responsiveness. CD28, CTLA4 and GITR s and fl mRNA levels in CD4+CD25+ T regulatory (Treg) cells from allo and autoBMT patients were significantly increased (7-, 41- or 22-fold, P&lt;0.01) compared to the CD4+CD25− subset. Additional studies attempted to identify the potential role of the sCTLA4 protein (encoded by the mRNA splice variant) on the regulation of the lymphocyte response mediated by Treg cells. Addition of the Treg cells to a mixed lymphocyte reaction suppressed the proliferative response of CD8+ T cells to alloantigens (75% suppression; &gt;4 fold reduction of 3H-thymidine incorporation). However, pretreatment of the Treg subset with short interfering RNA (siRNA) to knockdown sCTLA4 gene (confirmed by quantitative PCR) significantly reduced the ability of these cells to suppress the response (minimal suppression was detected, 6%). In vitro siRNA studies also indicated that Treg cells with inhibited sCTLA4 expression were unable to suppress the response of IL-2-stimulated autoreactive CD8+ T cells. Taken together, the results indicate that increased expression of CTLA4 (soluble and cell-surface associated) and the “negative” signal delivered by this molecule to the T cell may regulate the development of GVHD and help to re-establish self tolerance after BMT. Defining the role of costimulation and the modulation of this pathway on immune recognition and regulation not only provides opportunities to enhance the re-establishment of tolerance but also may help to intensify anti-tumor immunotherapeutic strategies.

CD4+ Regulatory T Cells Specific for the WT1 Antigen Are Present in Acute Myeloid Leukemia Patients: Implication for Immunotherapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1933-1933
Author(s):  
Said Dermime ◽  
Cynthia Lehe ◽  
Hazem Ghebeh ◽  
Abdullah Al-Sulaiman ◽  
Ghofran Al Qudaihi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Granzyme B ◽  
Critical Role ◽  
Leukemic Cells ◽  
Cell Contact

Abstract Compelling evidences indicate a key role for regulatory T cells (Tregs) on the host response to cancer and recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of Tregs. This is the first study to describe human Tregs generated specifically against the WT1 antigen which is overexpressed in several human leukemias and provide the mechanism by which these anti-WT1 Tregs inhibit the immune response in leukemia patients. We have generated T cell lines and clones that specifically recognized a WT1-84 peptide in an HLA DRB1*0402/TCR-Vb8-restricted manner. Importantly, they recognized HLADRB1* 04-matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a Th2 cytokine profile, had a CD4+CD25+Foxp3+GITR+CD127− Tregs phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell-contact. Priming of allo-reactive T cells in the presence of Tregs strongly inhibited the expansion of NK; NK-T and CD8+ T cells, had an inhibitory effect on NK/NK-T cytotoxic activity but not on CD8+ T cells. Furthermore, priming of T cells with the WT1- 126 HLA-A0201-restricted peptide in the presence of Tregs strongly inhibited the induction of anti-WT1-126 CD8+ CTL responses as evidenced by both very low cytotoxic activity and IFN-g production. Moreover, these Tregs clones specifically produced Granzyme-B and selectively induced apoptosis in WT1-84 pulsed-autologous APCs but not in apoptoticresistant DR4-matched leukemic cells. Importantly, we have also detected anti-WT1-84 IL-5+/Granzyme-B+/Foxp3+ CD4+ Tregs in 5 out of 8 HLA-DR4+ AML patients. These findings suggest a critical role for anti-WT1 Tregs in the inhibition of T cell responses against leukemia. This study may have important implications for the clinical manipulation of Tregs such as immuno-targeting of TCR-Vb-8 with mAbs to eliminate anti-WT1 Tregs in leukemia patients in order to enhance GVL before vaccination with the WT1 antigen. On the other hand, leukemia patients with GVHD should be clinically-tried for vaccination with the current WT1-84 peptide or adoptively-treated with ex-vivo anti-WT1 Treg cells to specifically enhance their frequency, which is known to be very low in these patients.

PI3K-Independent Signaling Pathways Contribute to ICOS-Mediated T-Cell Costimulation in Acute Graft-Versus-Host Disease in Mice.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3003-3003
Author(s):  
Jun Li ◽  
Julie Leconte ◽  
Kenrick Semple ◽  
Jessica Heinrichs ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Acute Gvhd ◽  
Calcium Flux ◽  
Pi3k Signaling ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Abstract 3003 ICOS provides an important costimulation to promote T-cell activation and function. Using a knock-in mouse strain, termed ICOS-YF, in which the cytoplasmic tail of ICOS cannot activate phosphoinositide 3-kinase (PI3K), we have shown that ICOS-PI3K signaling axis is critical for the generation of follicular helper T cells. We also observed that, in both CD4+ and CD8+ T cells, ICOS could potentiate TCR-mediated calcium flux in a PI3K-independent manner in vitro. Although ICOS can potentiate TCR-mediated calcium flux independent of PI3K, its biological significance is unclear. To address this question, we studied the function of ICOS-YF T cells in comparison with ICOS wild-type (WT) and knock-out (KO) T cells in MHC-mismatched bone marrow transplantation (BMT) models. Severity of acute graft-versus-host disease (GVHD) was evaluated based on recipient survival, body weight change, and pathologic scores. Consistent with the data previously published by us and others, ICOS KO T cells had significantly reduced ability to cause acute GVHD as compared to WT T cells. We further observed that YF T cells were significantly more capable in causing GVHD than KO T cells, but less capable than WT T cells. Mechanically, the levels of serum TNFa and IFNg were similar in the recipients of YF or KO T cells, but significantly lower than those of WT T cells. However, on the per-cell basis, YF CD8+ T cells expressed similar levels of intracellular IFNg as WT T cells, but significantly higher than KO T cells. We further compared the ability of CD4+ or CD8+ T cells alone in the induction of acute GVHD, and found that CD4+ T cells from YF and KO mice were similarly impaired in their capacity to induce acute GVHD. In contrast, the pathogenic capacity of CD8+ T cells from YF mice was comparable to that of WT cells, whereas KO CD8+ T cells were significantly less pathogenic. These results suggest that although both CD4+ and CD8+ T cells depend on ICOS costimulation, the downstream signaling pathways they utilize are distinct: CD4+ T cells depend on ICOS-PI3K signaling whereas CD8+ T cells are more dependent on PI3K-independent pathways, probably calcium signaling. Taken together, our study reveals a complexity in ICOS signaling mechanisms in T cell activation and GVHD induction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction

2014 ◽  
Vol 211 (10) ◽  
pp. 2047-2059 ◽  
Author(s):  
Peter D. Kurktschiev ◽  
Bijan Raziorrouh ◽  
Winfried Schraut ◽  
Markus Backmund ◽  
Martin Wächtler ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Critical Role ◽  
Interferon Γ ◽  
Strongly Correlated

The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet–deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet+ CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.

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