scholarly journals TIMs: central regulators of immune responses

2008 ◽  
Vol 205 (12) ◽  
pp. 2699-2701 ◽  
Author(s):  
David A. Hafler ◽  
Vijay Kuchroo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Infections ◽  
Opportunistic Infections ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Responses ◽  
Chronic Viral Infections ◽  
Chronic Hiv Infection

Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.

scholarly journals Impact of Epitope Escape on PD-1 Expression and CD8 T-Cell Exhaustion during Chronic Infection

2009 ◽  
Vol 83 (9) ◽  
pp. 4386-4394 ◽  
Author(s):  
Joseph N. Blattman ◽  
E. John Wherry ◽  
Sang-Jun Ha ◽  
Robbert G. van der Most ◽  
Rafi Ahmed
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Viral Clearance ◽  
T Cell Exhaustion ◽  
Wild Type ◽  
Cell Exhaustion ◽  
Cell Responses ◽  
Functional Inactivation

ABSTRACT During some persistent viral infections, virus-specific T-cell responses wane due to the antigen-specific deletion or functional inactivation (i.e., exhaustion) of responding CD8 T cells. T-cell exhaustion often correlates with high viral load and is associated with the expression of the inhibitory receptor PD-1. In other infections, functional T cells are observed despite high levels of pathogen persistence. The reasons for these different T-cell fates during chronic viral infections are not clear. Here, we tracked the fate of virus-specific CD8 T cells in lymphocytic choriomeningitis virus (LCMV)-infected mice during viral clearance, the persistence of wild-type virus, or the selection and persistence of a viral variant that abrogates the presentation of a single epitope. Viral clearance results in PD-1lo functional virus-specific CD8 T cells, while the persistence of wild-type LCMV results in high PD-1 levels and T-cell exhaustion. However, following the emergence of a GP35V→A variant virus that abrogates the presentation of the GP33 epitope, GP33-specific CD8 T cells remained functional, continued to show low levels of PD-1, and reexpressed CD127, a marker of memory T-cell differentiation. In the same animals and under identical environmental conditions, CD8 T cells recognizing nonmutated viral epitopes became physically deleted or were PD-1hi and nonfunctional. Thus, the upregulation of PD-1 and the functional inactivation of virus-specific T cells during chronic viral infection is dependent upon continued epitope recognition. These data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.

scholarly journals Tumor-Specific T Cells in Human Merkel Cell Carcinomas: A Possible Role for Tregs and T-Cell Exhaustion in Reducing T-Cell Responses

2013 ◽  
Vol 133 (7) ◽  
pp. 1879-1889 ◽  
Author(s):  
Mitra Dowlatshahi ◽  
Victor Huang ◽  
Ahmed E. Gehad ◽  
Ying Jiang ◽  
Adam Calarese ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Exhaustion ◽  
Merkel Cell ◽  
Cell Exhaustion ◽  
Cell Responses

scholarly journals Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses

2015 ◽  
Vol 84 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Tomohiro Okagawa ◽  
Satoru Konnai ◽  
Asami Nishimori ◽  
Ryoyo Ikebuchi ◽  
Seiko Mizorogi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Avium ◽  
T Cell Responses ◽  
T Cell Exhaustion ◽  
Content Type ◽  
Cell Exhaustion ◽  
Mhc Ii ◽  
Cell Responses ◽  
Ifn Γ

Johne's disease (paratuberculosis) is a chronic enteritis in cattle that is caused by intracellular infection withMycobacterium aviumsubsp.paratuberculosis. This infection is characterized by the functional exhaustion of T-cell responses toM. aviumsubsp.paratuberculosisantigens during late subclinical and clinical stages, presumably facilitating the persistence of this bacterium and the formation of clinical lesions. However, the mechanisms underlying T-cell exhaustion in Johne's disease are poorly understood. Thus, we performed expression and functional analyses of the immunoinhibitory molecules programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC-II) inM. aviumsubsp.paratuberculosis-infected cattle during the late subclinical stage. Flow cytometric analyses revealed the upregulation of PD-1 and LAG-3 in T cells in infected animals, which suffered progressive suppression of interferon gamma (IFN-γ) responses to theM. aviumsubsp.paratuberculosisantigen. In addition, PD-L1 and MHC-II were expressed on macrophages from infected animals, consistent with PD-1 and LAG-3 pathways contributing to the suppression of IFN-γ responses during the subclinical stages ofM. aviumsubsp.paratuberculosisinfection. Furthermore, dual blockade of PD-L1 and LAG-3 enhancedM. aviumsubsp.paratuberculosis-specific IFN-γ responses in blood from infected animals, andin vitroLAG-3 blockade enhanced IFN-γ production fromM. aviumsubsp.paratuberculosis-specific CD4+and CD8+T cells. Taken together, the present data indicate thatM. aviumsubsp.paratuberculosis-specific T-cell exhaustion is in part mediated by PD-1/PD-L1 and LAG-3/MHC-II interactions and that LAG-3 is a molecular target for the control ofM. aviumsubsp.paratuberculosis-specific T-cell responses.

scholarly journals Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema

2021 ◽  
Vol 11 ◽  
Author(s):  
Sacha Horn ◽  
Dennis Borrero-Wolff ◽  
Manuel Ritter ◽  
Kathrin Arndts ◽  
Anna Wiszniewsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Wuchereria Bancrofti ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Memory Cd8 T Cells ◽  
Cell Exhaustion ◽  
And Control ◽  
Control Management

CD8+ T cells are crucial for the clearance of viral infections, and current research begins to highlight their importance in parasitic diseases too. In-depth research about characteristics of CD8+ T-cell subsets and exhaustion remains uncertain, especially during filariasis, a chronic helminth infection. Lymphatic filariasis, elicited by Wuchereria bancrofti, remains a serious health problem in endemic areas in Ghana, especially in those suffering from morbidity due to lymphedema (LE). In this observational study, the characteristics and profiles of CD8+ T cells were compared between asymptomatic Wuchereria bancrofti-infected individuals, uninfected endemic normals, and those with LE (grades 2–6). Focusing on exhausted memory (CD8+exmem: CD8+ T-betdimEomeshi) and effector (CD8+exeff: CD8+T-bethiEomesdim) CD8+ T-cell subsets, advanced flow cytometry revealed that LE individuals presented reduced frequencies of IFN-γ+CD8+exmem T cells expressing Tim-3 or LAG-3 which negatively correlated to the presence of LE. Moreover, the LE cohort further showed significantly higher frequencies of IL-10+CD8+exeff T cells expressing either Tim-3, LAG-3, CD39, KLRG-1, or PD-1, all associated markers of exhaustion, and that these frequencies positively correlated with the presence of LE. In summary, this study shows that distinct exhausted CD8+ T-cell subsets are prominent in individuals suffering from LE, suggesting that enhanced inflammation and constant immune activation might drive exhaustion of CD8+ T cells. Since T-cell exhaustion is known to be associated with insufficient control of persisting antigen, the data presented here reveals that these CD8+ T-cell exhaustion patterns in filarial LE should be taken into consideration for prevention and control management of LE.

scholarly journals Control of T Cell Responses, Tolerance and Autoimmunity by Regulatory T Cells: Current Concepts

2003 ◽  
Vol 46 (4) ◽  
pp. 131-137 ◽  
Author(s):  
Pavel Chrobák
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cell Responses ◽  
Chronic Viral Infections ◽  
And Function ◽  
Special Circumstances ◽  
Immunosuppressive Cytokines

Regulatory T cells have emerged as an important mechanism of regulating tolerance and T cell responses. CD4+ regulatory T cells can be divided into two main groups, natural regulatory T cells, which express high levels of CD25 on their cell surface and phenotypically diverse adaptive (antigen induced) regulatory T cells. Natural regulatory T cells are made in the thymus, and require strong costimulatory signals for induction and maintenance, express a transcription factor called Foxp3, and function by a largely unknown mechanism. Adaptive (antigen induced) regulatory T cells are made by sub-optimal antigenic signals in the periphery, in the presence of immunosuppressive cytokines, often in special circumstances, such as chronic viral infections or after mucosal administration of antigen, and rely on cytokines such as IL-10 and TGF-β for suppression. Regulatory T cells offer a great potential for the treatment of autoimmune diseases and during transplantation.

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 Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells

2017 ◽  
Vol 114 (13) ◽  
pp. E2776-E2785 ◽  
Author(s):  
Giuliana P. Mognol ◽  
Roberto Spreafico ◽  
Victor Wong ◽  
James P. Scott-Browne ◽  
Susan Togher ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Tumor Infiltrating Lymphocytes ◽  
Chromatin Accessibility ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Persistent Antigen ◽  
Infiltrating Lymphocytes

T-cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8+ tumor-infiltrating lymphocytes (TILs) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, nonexhausted TILs and in acutely restimulated CD8+ T cells, we define a pattern of chromatin accessibility specific for T-cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti–PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TILs, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T-cell exhaustion in cancer and other inflammatory settings.

scholarly journals Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8+T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

2015 ◽  
Vol 89 (7) ◽  
pp. 3723-3736 ◽  
Author(s):  
Kiera L. Clayton ◽  
Matthew B. Douglas-Vail ◽  
A. K. M. Nur-ur Rahman ◽  
Karyn E. Medcalf ◽  
Irene Y. Xie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Disease Progression ◽  
Human Plasma ◽  
Soluble Form ◽  
Hiv Disease ◽  
Cell Exhaustion ◽  
Domain 3 ◽  
Chronic Hiv Infection

ABSTRACTChronic HIV infection results in a loss of HIV-specific CD8+T cell effector function, termed “exhaustion,” which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8+T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8+T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions.IMPORTANCEDespite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.

scholarly journals Immunotherapeutic effects of IL-7 during a chronic viral infection in mice

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5123-5132 ◽  
Author(s):  
Som G. Nanjappa ◽  
Eui Ho Kim ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
T Cell Responses ◽  
Duration Of Treatment ◽  
Viral Control ◽  
Cell Responses ◽  
Chronic Viral Infections

AbstractViral persistence during chronic viral infections is associated with a progressive loss of T-cell effector function called functional exhaustion. There is therefore a need to develop immunotherapies to remediate the functional deficits of T cells during these infections. We investigated the immunotherapeutic effects of IL-7 during chronic lymphocytic choriomeningitis virus infection in mice. Our results showed that the effects of IL-7 on T cells depend on the viral load, timing, and duration of treatment during the course of the infection. We document that the effectiveness of IL-7 was constrained by high viral load early in the infection, but treatment for at least 3 weeks during declining viral titers mitigated the programmed contraction of CD8 T cells, markedly enhanced the number of high-quality polyfunctional virus-specific CD8 T cells with a nonexhausted phenotype, and accelerated viral control. Mechanistically, the enhancement of CD8 T-cell responses by IL-7 was associated with increased proliferation and induction of Bcl-2, but not with altered levels of PD-1 or Cbl-b. In summary, our results strongly suggest that IL-7 therapy is a potential strategy to bolster the quality and quantity of T-cell responses in patients with chronic viral infections.

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