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 CD8+CD44hi but not CD4+CD44hi memory T cells mediate potent graft antilymphoma activity without GVHD

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3230-3239 ◽  
Author(s):  
Suparna Dutt ◽  
Jeanette Baker ◽  
Holbrook E. Kohrt ◽  
Neeraja Kambham ◽  
Mrinmoy Sanyal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Effector Memory ◽  
T Cell Subset ◽  
Progressive Growth

Abstract Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL1) without GVHD after recipients were given T cell–depleted bone marrow transplantations from major histocompatibility complex–mismatched donors. Lethal GVHD was observed when total T cells, naive CD4+ T cells, or naive CD8+ T cells were used. Memory CD4+CD44hi and CD8+CD44hi T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8+ T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8+ memory T cells after transplantation was able to eradicate the BCL1 lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8+ T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4+ T cells, or memory total T cells.

scholarly journals The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice.

1988 ◽  
Vol 167 (5) ◽  
pp. 1713-1718 ◽  
Author(s):  
T J Santoro ◽  
J P Portanova ◽  
B L Kotzin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Treatment ◽  
Cell Subset ◽  
Dramatic Reduction ◽  
Autoantibody Production ◽  
T Cell Subset

The current study examines the role of the L3T4 T cell subset in the development of lupus-like autoimmunity and lymphoproliferation in lpr-bearing mice. Chronic treatment of MRL-lpr/lpr mice with anti-L3T4 antibody beginning at 4 wk old was found to markedly decrease the production of IgG anti-DNA and antihistone antibodies, while having no effect on IgM autoantibodies. A dramatic reduction in splenomegaly and lymphadenopathy was also observed coincident with a decrease in the percentage and total number of Thy-1+, B220+ cells. Together, the data suggest an important role for L3T4+ T cells in the pathogenesis of disease in lpr mice and provide further evidence that a requirement for the L3T4 subset may be a common feature of murine autoimmunity.

scholarly journals CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells in mice

2020 ◽  
Author(s):  
Takayoshi Yamauchi ◽  
Toshifumi Hoki ◽  
Takaaki Oba ◽  
Kristopher Attwood ◽  
Xuefang Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cell Subset ◽  
Antitumor Efficacy ◽  
Preclinical Model ◽  
Therapeutic Vaccines ◽  
T Cell Subset

AbstractThe use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 vaccination and the generation of antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination, suggesting that the expanded CX3CR1+ CD8+ T cell subset represents the post-differentiated in vivo effective CX3CR1-negative CD8+ T cell subset. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.

Complementary Costimulation of Human T Cell Subpopulations by CD28 and CD81

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1124-1124
Author(s):  
Shoshana Levy ◽  
Yael Sagi
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Cell Subset ◽  
T Cell Subsets ◽  
T Cell Subset ◽  
Human T Cell

Abstract Abstract 1124 CD81 is a widely expressed tetraspanin molecule that physically associates with CD4 and CD8 on the surface of human T cells. Coengagement of CD81 and CD3 results in the activation and proliferation of T cells. CD81 also costimulated mouse T cells that lack CD28, suggesting either a redundant or a different mechanism of action. Here we show that CD81 and CD28 have a preference for different subsets of T cells - primary human naïve T cells are better costimulated by CD81, while the memory T cell subsets and Tregs are better costimulated by CD28. The more efficient activation of naïve T cells by CD81 was due to prolonged signal transduction compared to that by CD28. We found that IL-6 played a role in the activation of the naïve T cell subset by CD81. Combined costimulation through both CD28 and CD81 resulted in an additive effect on T cell activation. Thus, these two costimulatory molecules complement each other both in the strength of signal transduction and in T cell subset inclusions. Costimulation via CD81 might be useful for expansion of T cells for adoptive immunotherapy to allow the inclusion of naïve T cells with their broad repertoire. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Annexin A5 is essential for PKCθ translocation during T-cell activation

2020 ◽  
Vol 295 (41) ◽  
pp. 14214-14221
Author(s):  
Zhaoqing Hu ◽  
Lin Li ◽  
Banghui Zhu ◽  
Yi Huang ◽  
Xinran Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Adaptive Immune System ◽  
Annexin A5 ◽  
Activated T Cells ◽  
Calcium Dependent

T-cell activation is a critical part of the adaptive immune system, enabling responses to foreign cells and external stimulus. In this process, T-cell antigen receptor (TCR) activation stimulates translocation of the downstream kinase PKCθ to the membrane, leading to NF-κB activation and thus transcription of relevant genes. However, the details of how PKCθ is recruited to the membrane remain enigmatic. It is known that annexin A5 (ANXA5), a calcium-dependent membrane-binding protein, has been reported to mediate PKCδ activation by interaction with PKCδ, a homologue of PKCθ, which implicates a potential role of ANXA5 involved in PKCθ signaling. Here we demonstrate that ANXA5 does play a critical role in the recruitment of PKCθ to the membrane during T-cell activation. ANXA5 knockout in Jurkat T cells substantially inhibited the membrane translocation of PKCθ upon TCR engagement and blocked the recruitment of CARMA1-BCL10-MALT1 signalosome, which provides a platform for the catalytic activation of IKKs and subsequent activation of canonical NF-κB signaling in activated T cells. As a result, NF-κB activation was impaired in ANXA5-KO T cells. T-cell activation was also suppressed by ANAX5 knockdown in primary T cells. These results demonstrated a novel role of ANXA5 in PKC translocation and PKC signaling during T-cell activation.

scholarly journals Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI

Blood ◽  
2021 ◽  
Vol 137 (1) ◽  
pp. 126-137
Author(s):  
Julian C. Assmann ◽  
Don E. Farthing ◽  
Keita Saito ◽  
Natella Maglakelidze ◽  
Brittany Oliver ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Early Detection ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Cell Subset ◽  
Metabolic Imaging ◽  
Effector Memory ◽  
Hematopoietic Stem

Abstract Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.

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.

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