Late-emerging strains of HIV induce T-cell homeostasis failure by promoting bystander cell death and immune exhaustion in naïve CD4 and all CD8 T-cells

Abstract BACKGROUND: A subset of patients with Myelodysplastic Syndrome (MDS) responds well to immunosuppressive therapy (IST) and the only validated predictor of response is age, with younger patients faring much better than older patients. Hematologic improvement on immunosuppressive therapy is associated with a survival benefit with response rates ranging from 15% to 50%, clearly comparable or better than results with other existing therapies in MDS. Despite progress in the basic understanding of immune pathobiology of MDS and a clear therapeutic value, including improved long-term survival, IST including anti-thymocyte globulin (ATG) and/or cyclosporine A (CyA) is rarely offered to MDS patients in the U.S. due to uncertain criteria for selection of patients and potential toxicities. In addition, there is an underlying concern that inappropriate use of immunosuppressive therapy may negatively impact risk for leukemia progression, which occurs in 30–40% of MDS cases. The long-term goal of this study is to identify an immune signature that has postive predictive power for IST responsiveness. METHODS: To determine the effect of age on T-cell homeostasis and function and IST response, we performed a study of 54 MDS patients compared to 37 healthy controls. In a pilot study, T cell abnormalities associated with response to equine anti-lymphocyte globulin (eATG, lymphoglobulin, Pfizer, Inc) and/or CyA was studied in 12 younger MDS patients composed of 6 responders and 6 non-responders. RESULTS: CD4+ T-cells are normally present in the peripheral blood lymphocyte pool at 2 to 4 times greater than that of CD8+ T-cells, and diminished CD4:CD8 ratio has been previously shown to correlate with poor survival outcome in MDS. Similar to previous reports, we found that the age-adjusted CD4:CD8 ratio was reduced in MDS patients compared to healthy controls (p-value <0.0001) Interestingly, our analysis revealed that inadequate CD4+ rather than expansion of CD8+ T-cells was associated with a lower ratio in this group of MDS patients that included both lower and higher risk MDS patients defined by the International Prognostic Scoring System (IPSS). Analysis of the percentage of T-cells with naïve and memory phenoytpes using CD45RA and CD62L display, demonstrated positive correlations between age and both % CD62L positive naïve cells and central memory CD4+ T-cells (naïve: slope=0.39, p=0.12; central memory: slope=1.26, p=0.005). Furthermore, the proportions of CD62L- CD4+ T-cell populations, including effector memory and terminal effector memory T-cells, were greater in younger MDS patients (slope=−0.82, p=0.08 and slope=−0.83, p=0.015, respectively) suggesting a possible relationship to IST responsiveness. Specific characteristics associated with response to eATG in the pilot study of 12 younger patients included altered distribution of T cell populations (i.e., lower CD4/CD8 ratio, p<0.001) and higher constitutive proliferative index of the T cell populations (p=0.03 CD4+ and p=0.02 CD8+ T-cells, respectively). We also found that hematological response was associated with blockade of homeostatic proliferation of T cells associated with reconstitution of the naïve T cell pool. Reduction in CD4+ T-cells and expansion of autoreactive CD8+ T-cells suggests that apoptotic conditions may drive the expansion of cells through homeostatic cytokines such as IL-7, IL-15, and/or IL-21, which are all cytokines of the IL-2Rγc family that control homeostatic proliferation. Comparisons of the IL-7Ra, IL-15Ra, IL-2Ra, and IL-21Ra subunit demonstrated overexpression of IL-21Ra in patients 35.4% ± 3.4 in CD4+ T-cells and 31.8% ± 4.3 in CD8+ T-cells compared to healthy donors 0.9% ± 0.5 and 0.5% ± 0.5 (p<0.0001). CONCLUSIONS: Association between the T-cell abnormalities reported in this study and response to IST strongly suggests that aberrant T-cell homeostasis may represent a critical determinant of autoimmunity in MDS that may have positive predictive power for response to IST.

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Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

Blood ◽

10.1182/blood-2008-05-156307 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4546-4554 ◽

Cited By ~ 70

Author(s):

Spencer W. Stonier ◽

Lisa J. Ma ◽

Eliseo F. Castillo ◽

Kimberly S. Schluns

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Memory Cd8 T Cells ◽

Specific Memory ◽

Memory Cd8 T Cell

AbstractInterleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15Rα+ DCs through the preferential enhancement of a subset of KLRG-1+CD27− CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis.

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Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates

Blood ◽

10.1182/blood-2010-01-263814 ◽

2010 ◽

Vol 116 (5) ◽

pp. 748-758 ◽

Cited By ~ 20

Author(s):

Jessica C. Engram ◽

Barbara Cervasi ◽

Jose A. M. Borghans ◽

Nichole R. Klatt ◽

Shari N. Gordon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Cell Repopulation

Abstract Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4+ or CD8+ lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4+ or CD8+ T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4+ and CD8+ lymphocyte depletions were followed by a largely lineage-specific CD4+ and CD8+ T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4+ T cells than RMs. In addition, in both species CD8+ T-cell repopulation was faster than that of CD4+ T cells, with CD8+ T cells reconstituting a normal pool within 60 days and CD4+ T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4+ T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4+ T-cell destruction is chronic.

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Gene Targeting of Cdc42 Reveals Its Essential Role in T Cell Development and Homeostasis.

Blood ◽

10.1182/blood.v110.11.794.794 ◽

2007 ◽

Vol 110 (11) ◽

pp. 794-794

Author(s):

Fukun Guo ◽

David Hildeman ◽

Jun Mo ◽

Yi Zheng

Keyword(s):

T Cells ◽

Cell Migration ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Essential Role ◽

T Cell Development ◽

Brdu Incorporation ◽

T Cell Homeostasis ◽

Cell Homeostasis

Abstract Cdc42 of the Rho GTPase family is known to play an essential role in diverse cell functions. Previous studies by using dominant mutants or transgenic mice suggest that Cdc42 is involved in T cell polarization, immune synapse formation, migration, and development. Because the dominant mutant overexpressing approach imposes significant experimental limitations, we have characterized the T cell-specific, conditional gene targeted mice with the Lck-Cre;Cdc42loxP/loxP genotype in an effort to define the physiological role of Cdc42. Firstly, Cdc42 gene disruption in T cells caused an increase of CD4+CD8+ double positive T cells by ∼10% whereas a reduction of both CD4+CD8− and CD4−CD8+ single positive T cells by >50% in the Cdc42−/ − thymus. The thymus of Cdc42-deleted mice showed small and inconspicuous thymic medulla and the thymic cortex of Cdc42-deficient mice appeared prominent. Examination of CD69 expression in Cdc42−/ − CD4+CD8+ T cells revealed a defective positive selection. In peripheral organs, loss of Cdc42 caused a drastic reduction of mature T cell populations in lymph nodes, blood and spleens. Spleens of the Cdc42 null mice contained ∼1/7 of CD4+ T cells and ∼1/8 of CD8+ T cells compared with that of wild type (WT) mice. These phenotypic observations indicate that Cdc42 regulates T cell development and homeostasis. Secondly, the perturbed T cell homeostasis in Cdc42 null mice is associated with defective T cell survival characterized by an increase in apoptosis and a gain of resistance to IL-7-mediated cell survival. The apoptotic phenotype of Cdc42−/ − T cells correlates with an increased expression of pro-apoptotic Fas and decreased expression of anti-apoptotic BCL-2. Concomitantly, Cdc42 deficiency resulted in an increase in homeostatic proliferation as manifested by increased in vivo BrdU incorporation in Cdc42-deficient T cells and accelerated division of Cdc42 null cells upon adoptive transfer into Rag2−/ − mice, possibly due to a compensatory effect of lymphopenia. Thus, a combined effect on survival and proliferation by Cdc42 deficiency may contribute to the defective T cell homeostasis. Thirdly, F-actin assembly, T cell receptor (TCR) capping, and cell migration were impaired in T cells lacking Cdc42. Cdc42 deficiency caused a ∼50% reduction in the percentage of CD4+ T cells with capped TCR in response to TCR cross-linking. Chemotaxis of Cdc42−/ − CD4+ T cells toward SDF-1a was reduced by 40% in comparison with that of WT cells, suggesting that Cdc42 regulates T cell migration and polarization, which may also be involved in the defective homeostatic distribution of Cdc42−/ − T cells. Fourthly, Cdc42 deficiency appears to promote the activation of mature T cells with an elevated expression of a T cell activation marker, CD69. Cdc42−/ − T cells proliferated faster than WT cells and showed increased BrdU incorporation upon in vitro culture with CD3 antibody. This activation phenotype may be attributed to a constitutively elevated ERK activity found in the Cdc42−/ − T cells. Finally, loss of Cdc42 led to an increase of naturally-occurring and the lymphocytic choriomeningitis virus-specific effector and memory T cells. Autoimmune-protective CD4+CD25+ regulatory T cells were markedly reduced and the production of T helper cell-dependent IgG2a increased by ∼6 folds in the absence of Cdc42. Taken together, our results suggest that Cdc42 plays a critical role in T cell homeostasis by regulating survival and proliferation. Further, Cdc42 is important for T cell actin cytoskeleton rearrangement, polarization and migration and for effector and memory T cell response.

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CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1602899113 ◽

2016 ◽

Vol 113 (29) ◽

pp. 8278-8283 ◽

Cited By ~ 25

Author(s):

Yong Woo Jung ◽

Hyun Gyung Kim ◽

Curtis J. Perry ◽

Susan M. Kaech

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Memory T Cells ◽

Cd8 T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Memory Cd8 T Cells ◽

Ccr7 Expression ◽

Memory Cd8 T Cell

C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7−/− memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7–dependent niches over IL-15–dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets.

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T cells at work: how post‐transcriptional mechanisms control T cell homeostasis and activation

European Journal of Immunology ◽

10.1002/eji.202049055 ◽

2021 ◽

Author(s):

Anouk P. Jurgens ◽

Branka Popović ◽

Monika C. Wolkers

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis

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Adoptive transfer of syngeneic T cells in HIV-1 discordant twins indicates rapid regulation of T-cell homeostasis

British Journal of Haematology ◽

10.1111/j.1365-2141.2006.06478.x ◽

2007 ◽

Vol 136 (4) ◽

pp. 641-648 ◽

Cited By ~ 6

Author(s):

Christian Hoffmann ◽

Hans-Juergen Stellbrink ◽

Thomas Dielschneider ◽

Olaf Degen ◽

Albrecht Stoehr ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Adoptive Transfer ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Discordant Twins ◽

Hiv 1

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596 Combining Bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) pairs local innate activation with systemic CD8+ T cell expansion to enhance anti-tumor immunity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.596 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A626-A626

Author(s):

Annah Rolig ◽

Daniel Rose ◽

Grace Helen McGee ◽

Saul Kivimae ◽

Werner Rubas ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Immune Responses ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Response ◽

Cycle Phase ◽

Tumor Cell Death ◽

Specific Immunity

BackgroundTumor cell death caused by radiation therapy (RT) can trigger anti-tumor immune responses in part because dying cells release adjuvant factors that amplify and sustain DC and T cell responses. We previously demonstrated that bempegaldesleukin (BEMPEG:NKTR-214, a first-in-class CD122-preferential IL-2 pathway agonist), significantly enhanced the anti-tumor efficacy of RT through a T cell-dependent mechanism. Because RT can induce either immunogenic or tolerogenic cell death, depending on a multitude of factors (radiation dose, cell cycle phase, and tumor microenvironment), we hypothesized that providing a specific immunogenic adjuvant, like intratumoral NKTR-262, a novel toll-like receptor (TLR) 7/8 agonist, to the tumor site would further improve systemic tumor-specific immunity by promoting synergistic activation of local immunostimulatory innate immune responses. Therefore, we evaluated whether intratumoral NKTR-262, combined with systemic BEMPEG treatment would result in improved tumor-specific immunity and survival compared to BEMPEG combined with RT.MethodsTumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; iv), RT (16 Gy x 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+ and CD8+ T cell activation status in the blood and tumor (7 days post-treatment). The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+ T cell cytolytic activity was determined in vitro with an Incucyte assay. Data are representative of 1–2 independent experiments (n=5–14/group) and statistical significance was determined by 1-way ANOVA (p-value cut-off of 0.05).ResultsBEMPEG/NKTR-262 resulted in significantly improved survival compared to BEMPEG/RT. Both combination therapies were CD8+ T cell dependent. However, response to BEMPEG/NKTR-262 was characterized by a significant expansion of activated CD8+ T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, BEMPEG/NKTR-262 induced higher frequencies of GzmA+ CD8+ T cells exhibiting reduced expression of suppressive molecules (PD-1+, TIM-3+), compared to BEMPEG/RT. Additionally, CD8+ T cells isolated from BEMPEG/NKTR-262-treated tumors had greater cytolytic capacity than those from BEMPEG/RT-treated mice.ConclusionsCombining BEMPEG with NKTR-262 lead to a more robust expansion of activated CD8+ T cells compared to the BEMPEG/RT combination. Enhancement of the activated CD8+ T cell response in mice treated with NKTR-262 in combination with BEMPEG suggests that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared to RT. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

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Serum-derived exosomes promote CD8+ T cells to overexpress PD-1, affecting the prognosis of hypopharyngeal carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02294-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qian Gao ◽

Hui-Ting Liu ◽

Yu-Qin Xu ◽

Lin Zhang ◽

Yuan-Ru Liu ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cd8 T Cells ◽

Poor Prognosis ◽

Cell Function ◽

Immune Escape ◽

Cd8 T Cell ◽

Serum Exosomes

Abstract Background Hypopharyngeal cancer (HPC) is associated with a poor prognosis and a high recurrence rate. Immune escape is one of the reasons for the poor prognosis of malignant tumors. Programmed cell death ligand 1 (PD-L1) and programmed cell death-1 (PD-1) have been shown to play important roles in immune escape. However, the role of PD-1/PD-L1 in HPC remains unclear. In this experiment, we investigated the effect of exosomes from HPC patient serum on CD8+ T cell function and PD-1/PD-L1 expression and, thus, on prognosis. We hope to provide guidance for the identification of new targets for HPC immunotherapy. Methods PD-1 and CD8 expression in 71 HPC tissues and 16 paracarcinoma tissues was detected by immunohistochemistry. Concurrently, the clinicopathological data of the patients were obtained to conduct correlation analysis. Exosomes were isolated from serum and then identified by Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Flow cytometry was used to assess the activity of CD8+ T cells after exosome stimulation. The effects of exosomes on the ability of CD8+ T cells to kill FaDu cells were assessed by CCK-8 assay. The expression of IL-10 and TGF-β1 was measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in HPC tissue samples was evaluated by immunohistochemistry, and the relationship between PD-1/PD-L1 expression and prognosis was investigated with patient specimens. Results PD-1 expression was significantly upregulated on CD8+ T cells in tumor tissues compared with those in normal tissues. The overall survival (OS) and disease-free survival (DFS) of PD-1-overexpressing patients were decreased. Serum exosomes from patients can elevate PD-1 expression on CD8+ T cells and suppress their killing capacity and secretory function. The rate of positive PD-L1 expression was increased in HPC tissues compared with paracancerous tissues. The DFS and OS of the PD-1(+)-PD-L1(+) group were significantly lower than those of the PD-1(−)-PD-L1(−) group. Conclusion Our findings indicate that serum exosomes from HPC patients can inhibit CD8+ T cell function and that the PD-1-PD-L1 pathway plays an important role in the immune escape of HPC. Exosomes combined with immunotherapy may guide the treatment of patients with advanced disease in the future.

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Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a449 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Anna von Rossum ◽

Winnie Enns ◽

Yu P Shi ◽

Jonathan C Choy

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

T Cell Responses ◽

Intimal Thickening ◽

Cell Responses ◽

Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

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