scholarly journals Expanded antigen-experienced CD160+CD8+effector T cells exhibit impaired effector functions in chronic lymphocytic leukemia

2021 ◽  
Vol 9 (4) ◽  
pp. e002189
Author(s):  
Najmeh Bozorgmehr ◽  
Isobel Okoye ◽  
Olaide Oyegbami ◽  
Lai Xu ◽  
Amelie Fontaine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion ◽  
Effector Functions ◽  
Cell Effector

BackgroundT cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL.MethodsWe studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls.ResultsWe found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160+CD8+ T cells were highly antigen-experienced/effector T cells, while CD160+CD4+ T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160.ConclusionsOur study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.

scholarly journals Nicotinamide Inhibits T Cell Exhaustion and Increases Differentiation of CD8 Effector T Cells

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 323
Author(s):  
Sara Alavi ◽  
Abdullah Al Emran ◽  
Hsin-Yi Tseng ◽  
Jessamy C. Tiffen ◽  
Helen Marie McGuire ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Effector T Cells ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion ◽  
Terminal Effector

One of the limitations of immunotherapy is the development of a state referred to as T cell exhaustion (TEx) whereby T cells express inhibitory receptors (IRs) and lose production of effectors involved in killing of their targets. In the present studies we have used the repeated stimulation model with anti CD3 and anti CD28 to understand the factors involved in TEx development and treatments that may reduce changes of TEx. The results show that addition of nicotinamide (NAM) involved in energy supply to cells prevented the development of inhibitory receptors (IRs). This was particularly evident for the IRs CD39, TIM3, and to a lesser extent LAG3 and PD1 expression. NAM also prevented the inhibition of IL-2 and TNFα expression in TEx and induced differentiation of CD4+ and CD8 T cells to effector memory and terminal effector T cells. The present results showed that effects of NAM were linked to regulation of reactive oxygen species (ROS) consistent with previous studies implicating ROS in upregulation of TOX transcription factors that induce TEx. These effects of NAM in reducing changes of TEx and in increasing the differentiation of T cells to effector states appears to have important implications for the use of NAM supplements in immunotherapy against cancers and viral infections and require further exploration in vivo.

scholarly journals Single-Cell Transcriptome Analysis Reveals RGS1 as a New Marker and Promoting Factor for T-Cell Exhaustion in Multiple Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunmeng Bai ◽  
Meiling Hu ◽  
Zixi Chen ◽  
Jinfen Wei ◽  
Hongli Du
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Poor Prognosis ◽  
Effector T Cells ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Transcriptome ◽  
Cancer Tissues ◽  
Single Cell Transcriptome

T-cell exhaustion is one of the main reasons of tumor immune escape. Using single-cell transcriptome data of CD8+ T cells in multiple cancers, we identified different cell types, in which Pre_exhaust and exhausted T cells participated in negative regulation of immune system process. By analyzing the coexpression network patterns and differentially expressed genes of Pre_exhaust, exhausted, and effector T cells, we identified 35 genes related to T-cell exhaustion, whose high GSVA scores were associated with significantly poor prognosis in various cancers. In the differentially expressed genes, RGS1 showed the greatest fold change in Pre_exhaust and exhausted cells of three cancers compared with effector T cells, and high expression of RGS1 was also associated with poor prognosis in various cancers. Additionally, RGS1 protein was upregulated significantly in tumor tissues in the immunohistochemistry verification. Furthermore, RGS1 displayed positive correlation with the 35 genes, especially highly correlated with PDCD1, CTLA4, HAVCR2, and TNFRSF9 in CD8+ T cells and cancer tissues, indicating the important roles of RGS1 in CD8+ T-cell exhaustion. Considering the GTP-hydrolysis activity of RGS1 and significantly high mRNA and protein expression in cancer tissues, we speculated that RGS1 potentially mediate the T-cell retention to lead to the persistent antigen stimulation, resulting in T-cell exhaustion. In conclusion, our findings suggest that RGS1 is a new marker and promoting factor for CD8+ T-cell exhaustion and provide theoretical basis for research and immunotherapy of exhausted cells.

scholarly journals Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion

2018 ◽  
Vol 115 (10) ◽  
pp. 2455-2460 ◽  
Author(s):  
Lyndsay Avery ◽  
Jessica Filderman ◽  
Andrea L. Szymczak-Workman ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Chronic Infection ◽  
Cell Activation ◽  
Effector T Cells ◽  
Mtor Signaling ◽  
T Cell Exhaustion ◽  
Inhibitory Protein ◽  
Cell Exhaustion

Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3–deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, and may also contribute to exhaustion by restricting the development of long-lived memory T cells. Taken together, our results suggest that Tim-3 is actually more similar to costimulatory receptors that are up-regulated after T cell activation than to a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti–Tim-3 antibodies as therapeutic agents.

scholarly journals Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Eileen A. Wong ◽  
Louis Joslyn ◽  
Nicole L. Grant ◽  
Edwin Klein ◽  
Philana Ling Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Cell Activity ◽  
Intrinsic Property ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Content Type ◽  
Cell Exhaustion

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

scholarly journals Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

2021 ◽  
Author(s):  
Yini Sun ◽  
Renyu Ding ◽  
Yukun Chang ◽  
Jiuming Li ◽  
Xiaochun Ma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crucial Role ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

scholarly journals T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production

Blood ◽  
2013 ◽  
Vol 121 (9) ◽  
pp. 1612-1621 ◽  
Author(s):  
John C. Riches ◽  
Jeffrey K. Davies ◽  
Fabienne McClanahan ◽  
Rewas Fatah ◽  
Sameena Iqbal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Interferon Γ ◽  
Lymphocytic Leukemia ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
And Function ◽  
Functional Defects

Abstract T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8+ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFα and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)–specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL.

scholarly journals Tim-3 co-stimulation promotes short-term effector T cells, restricts memory precursors and is dispensable for T cell exhaustion

2017 ◽  
Author(s):  
Lyndsay Avery ◽  
Andrea L. Szymczak-Workman ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Effector T Cells ◽  
Chronic Viral Infection ◽  
T Cell Exhaustion ◽  
Inhibitory Protein ◽  
Cell Exhaustion

AbstractTim-3 is highly expressed on a subset of T cells during T cell exhaustion, in settings of chronic viral infection and tumors (1, 2). Using LCMV Clone-13, a model for chronic infection, we have found that Tim-3 is neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted development of short-term effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3 deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, but may also contribute to exhaustion, by restricting development of long-lived memory T cells, including PD-1int “stem-like” exhausted T cells that expand during PD-1 pathway blockade. Taken together, our results suggest that Tim-3 is actually more similar to co-stimulatory receptors that are upregulated after T cell activation, rather than a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti-Tim-3 antibodies as therapeutic agents.SignificanceDuring a chronic viral infection, prolonged exposure to viral antigens leads to dysfunction or “exhaustion” of T cells specific to the virus, a condition also observed in T cells that infiltrate tumors. The exhausted state is associated with expression of specific cell-surface proteins, some of which may inhibit T cell activation. Expression of Tim-3 is associated with acquisition of T cell exhaustion, although it is also expressed transiently during acute infection. Here we provide evidence that a major function of Tim-3 is to enhance T cell activation, during either acute or chronic viral infection. However, Tim-3 is not required for development of exhaustion. Thus, we propose that Tim-3 would be better described as a stimulatory, rather than inhibitory, protein.

Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 604-613 ◽  
Author(s):  
Tamara Kögl ◽  
Jürgen Müller ◽  
Birthe Jessen ◽  
Annette Schmitt-Graeff ◽  
Gritta Janka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cytolytic Activity ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion ◽  
Syntaxin 11 ◽  
Deficient Mice

Abstract Syntaxin-11 (Stx11), an atypical member of the SNARE protein family, is part of the cytolytic machinery of T and NK cells and involved in the fusion of lytic granules with the plasmamembrane. Functional loss of syntaxin-11 in humans causes defective degranulation and impaired cytolytic activity of T and NK cells. Furthermore, patients with STX11 deficiency develop familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a life-threatening disease of severe hyperinflammation. We established Stx11-deficient mice as an animal model for FHL4. Stx11-deficient mice exhibited severely reduced degranulation and cytolytic activity of CTL and NK cells and developed all clinical symptoms of hemophagocytic lymphohistiocytosis (HLH) after infection with lymphocytic choriomeningitis virus (LCMV). The HLH phenotype was further characterized by hyperactive CD8 T cells and continuous IFN-γ production. However, in contrast to perforin-deficient mice, which represent a model for FHL2, progression of HLH was not fatal. Survival of Stx11-deficient mice was determined by exhaustion of antigen-specific T cells, characterized by expression of inhibitory receptors, sequential loss of effector functions, and finally T-cell deletion. Blockade of inhibitory receptors on T cells in Stx11-deficient mice converted nonfatal disease course into fatal HLH, identifying T-cell exhaustion as an important factor for determination of disease severity in HLH.

scholarly journals Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2274
Author(s):  
Didem Saka ◽  
Muazzez Gökalp ◽  
Betül Piyade ◽  
Nedim Can Cevik ◽  
Elif Arik Sever ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Single Agent ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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