scholarly journals Functional and Phenotypic Characterization of CD57+CD4+T Cells and Their Association with HIV-1-Induced T Cell Dysfunction

2005 ◽  
Vol 175 (12) ◽  
pp. 8415-8423 ◽  
Author(s):  
Brent E. Palmer ◽  
Naomi Blyveis ◽  
Andrew P. Fontenot ◽  
Cara C. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Phenotypic Characterization ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Hiv 1

scholarly journals Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

2008 ◽  
Vol 205 (12) ◽  
pp. 2763-2779 ◽  
Author(s):  
R. Brad Jones ◽  
Lishomwa C. Ndhlovu ◽  
Jason D. Barbour ◽  
Prameet M. Sheth ◽  
Aashish R. Jha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Surface Expression ◽  
Cell Dysfunction ◽  
Cd38 Expression ◽  
Immunodeficiency Virus ◽  
T Cell Dysfunction ◽  
Novel Target ◽  
Hiv 1

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8+ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4+ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8+ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.

scholarly journals Programmed Death 1 Expression on HIV-Specific CD4+T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

2007 ◽  
Vol 179 (3) ◽  
pp. 1979-1987 ◽  
Author(s):  
Michelle D’Souza ◽  
Andrew P. Fontenot ◽  
Doug G. Mack ◽  
Catherine Lozupone ◽  
Stephanie Dillon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
Cell Dysfunction ◽  
Programmed Death ◽  
T Cell Dysfunction ◽  
Programmed Death 1

scholarly journals Differential Immune Responses in Epidemic and Endemic Tanzanian Kaposi Sarcoma Patients

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 202s-202s
Author(s):  
J.D. Mwaiselage ◽  
S. Lidenge ◽  
J.R. Ngowi ◽  
G. Haynatzki ◽  
C. Wood ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Immune Responses ◽  
Kaposi Sarcoma ◽  
Neutralizing Antibody ◽  
T Cell Differentiation ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Hiv 1

Background: Mechanisms underlying Kaposi sarcoma (KS) development are unclear. The high incidence of KS in HIV-1+ individuals implicates immune dysregulation in epidemic KS (EpKS) development. In African endemic KS (EnKS), the immune response is uncharacterized. Aim: The aim was to assess a comparative quantification between newly diagnosed Tanzanian EpKS and EnKS patients, and asymptomatic controls. We also report the first comparison of KSHV NAb prevalence and titer between EpKS and EnKS patients. Methods: To compare innate and adaptive immune responses, we recruited histologically confirmed Tanzanian EpKS and EnKS patients, as well as noncancer controls. After differential detection of KSHV nucleic acids in tissues, neutralizing antibody (NAb), levels of cytokines/chemokines, and T-cell differentiation subsets were quantified. The Mann-Whitney U-test was used to assess median differences between groups. All tests were 2-tailed and P-values < 0.05 were considered significant. Results: A total of 180 patients have been recruited in this study. In addition, a comparable 25 EpKS and 10 EnKS as well as 10 noncancer controls were recruited for this study. KSHV was significantly more frequently detected in EpKS patients than in EnKS. While all EpKS, and some EnKS patients mounted NAb responses, the EpKS patients had higher prevalence and titer of NAb compared with EnKS patients ( P = 0.001). Levels of the cytokines IP-10 and IL-10 were higher in EpKS vs EnKS patients ( P = 0.006 and P = 0.005 respectively), whereas, IL-4 was lower in EpKS vs EnKS patients ( P = 0.004). The levels of all 14 cytokines/chemokines measured were comparable between EnKS patients and HIV− controls ( P < .05 ). The distribution of CD4+ and CD8+ T-cells was similar between EpKS and EnKS such as naive and effector T-cells were depleted while central memory T-cells were elevated in both KS forms. Conclusion: The detection of similar abnormalities in T-cell differentiation subsets in both EpKS and EnKS as compared with controls, suggests that KSHV-induced T-cell dysfunction plays a major role in the disease, and that HIV-1 coinfection is only exacerbating and accelerating KSHV pathogenesis and KS development.

scholarly journals Emergence of Polyfunctional CD8+ T Cells after Prolonged Suppression of Human Immunodeficiency Virus Replication by Antiretroviral Therapy

2008 ◽  
Vol 82 (7) ◽  
pp. 3391-3404 ◽  
Author(s):  
Manuela Rehr ◽  
Julia Cahenzli ◽  
Anna Haas ◽  
David A. Price ◽  
Emma Gostick ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Functional Restoration ◽  
Cytokine Secretion ◽  
Cell Dysfunction ◽  
Immunodeficiency Virus ◽  
T Cell Dysfunction ◽  
Hiv 1

ABSTRACT Progressive human immunodeficiency virus type 1 (HIV-1) infection is often associated with high plasma virus load (pVL) and impaired CD8+ T-cell function; in contrast, CD8+ T cells remain polyfunctional in long-term nonprogressors. However, it is still unclear whether CD8+ T-cell dysfunction is the cause or the consequence of high pVLs. Here, we conducted a longitudinal functional and phenotypic analysis of virus-specific CD8+ T cells in a cohort of patients with chronic HIV-1 infection. During the initiation and maintenance of successful antiretroviral therapy (ART), we assessed whether the level of pVL was associated with the degree of CD8+ T-cell dysfunction. Under viremic conditions, HIV-specific CD8+ T cells were dysfunctional with respect to cytokine secretion (gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha), and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8+ T cells was gradually restored, IL-7Rα and CD28 expression increased dramatically, and PD-1 levels declined. Thus, prolonged ART-induced reduction of viral replication and, hence, presumably antigen exposure in vivo, allows a significant functional restoration of CD8+ T cells with the appearance of polyfunctional cells. These findings indicate that the level of pVL as a surrogate for antigen load has a dominant influence on the phenotypic and functional profile of virus-specific CD8+ T cells.

scholarly journals T Cell Dysfunction in Epstein-Barr Virus-Associated Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5310-5310
Author(s):  
Huihui Liu ◽  
Xinan Cen ◽  
Lihong Wang ◽  
Bingjie Wang ◽  
Yujun Dong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Barr Virus ◽  
Cell Dysfunction ◽  
Healthy Donors ◽  
T Cell Dysfunction ◽  
Epstein Barr ◽  
T Cell Senescence

Abstract The Epstein-Barr virus (EBV) is thought to be one of tumorigenic viruses, which can be detected in many kinds of lymphomas, such as extranodal NK/T-cell lymphoma and Burkitt lymphoma. Those EBV positive lymphomas are also called EBV-associated lymphomas. Some studies showed that patients with EBV-associated lymphoma had a worse prognosis. Dysfunction of T cells may contribute to failure of immune surveillance and tumorigenesis. Therefore, this study was aimed to investigate T cell dysfunction in patients with EBV-associated lymphoma. Peripheral blood was collected from 20 patients with EBV-associated lymphoma and 10 healthy donors (healthy EBV seropositive donors) at the Peking University First Hospital. First, the phenotypes and ratios of PBMCs were analyzed using flow cytometry. Compared with healthy donors, the proportion of CD3+ T cells were little lower in the patients, but had no significantly difference (healthy donors vs patients, 47.82±6.85% vs 34.43±3.63%, p=0.09). The ratios of CD4+ T cells / CD8+ T cells were significantly decreased in the patients, the proportion of CD4+ T cells in CD3+ T cells were decreased (healthy donors vs patients, 59.40±3.84% vs 29.46±2.84%, p<0.0001), and CD8+T cells in CD3+T cells were increased (healthy donors vs patients, 33.94±3.60% vs 57.36±2.59%, p=0.0003) in the patients. NK cells had no significantly difference between the two groups (healthy donors vs patients, 9.74±3.68% vs 10.37±2.16%, p=0.88). Further, an enzyme-linked immunospot assay revealed that the production of IFN-γ in T cells was remarkably reduced upon stimulation with EBV mixed peptides, suggesting EBV specific T responses were insufficient in the patients with EBV-associated lymphoma. To study the mechanism of T cells dysfunction in EBV-associated lymphoma, multiple inhibitory receptors were analyzed. Compared with healthy donors, we found that CD4+ T cells and CD8+ T cells expressed higher levels of PD-1, LAG-3, TIM-3 and CTLA-4 in the patients, suggesting T cells were exhausted in the patients with EBV-associated lymphoma. Furthermore, the T-bethi PD1mid exhausted T cells which can be rescued by blockade of PD1 pathway and the EOMEShi PD1hi exhausted T cells which can not be rescued by the blockade of PD1 pathway were both higher in the patients with EBV-associated lymphoma. CD57+KLRG-1+CD160+CD28- were markers of T cell senescence, we found this subset cells were also a little higher in patients, suggesting that T cell senescence might be another contributor of T cell dysfunction in the patients with EBV-associated lymphoma. In addition, some studies have demonstrated that exhausted T cells do not derive from the 'senescent' KLRG-1+ subset of effector T cells but rather from the CD127+ subset of memory precursors that are present in the effector phase. We found the proportion of CD127+ T cells reduced significantly in the patients, further suggesting memory T cells decreased and exhausted T cells increased in the patients with EBV-associated lymphoma. All together, we demonstrated here that T cell dysfunction was the predominant feature of the patients with EBV-associated lymphoma, including the T cells ratio imbalance and T cell exhaustion. Our study contributes to understand the pathogenesis of EBV-associated lymphoma and suggests that immune checkpoint blockade may be warranted. Disclosures No relevant conflicts of interest to declare.

Abstract 130: CD4 T Cell Dysfunction Induced to Endothelial Apoptosis in Peri-menopausal Women with Low Estrogen levels

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Keiko Gomita ◽  
Kayoko Sato ◽  
Toshiaki Nuki ◽  
Yuki Suzuki ◽  
Nobuhisa Hagiwara ◽  
...  
Keyword(s):  
T Cells ◽  
Estrogen Receptor ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Dysfunction ◽  
Plaque Erosion ◽  
Perimenopausal Women ◽  
T Cell Dysfunction ◽  
Coronary Syndromes

Background : Plaque erosion is responsible for the majority of acute coronary thrombi and induces acute coronary syndromes (ACS) in perimenopausal women. However, the causal relationship between low estrogen levels and plaque erosion mechanism in perimenopausal women is not fully understood. We examined whether perimenopausal women (PMW) with low levels of estrogen have had T cell dysfunction, and whether they experienced accelerated plaque erosion as a result. Methods and Results : Fresh CD4 T cells were isolated from 45 PMW within 5 years after menopause (mean age 53.9 ± 6.0 years) and 40 women with regular menstruation cycles (NC, mean age 34.0 ± 7.4 years). Estrogen levels in plasma were lower in PMW than NC (P < 0.0001). Estrogen receptor α (ESR1) and estrogen receptor β (ESR2) mRNA of CD4 T cells in PMW were lower compared to NC by real time PCR (P < 0.05). Estrogen levels correlated significantly with ESR1 transcripts (R = 0.537, P < 0.03). The inflammation marker of hsCRP was higher (P < 0.003) and CD69, an activation marker of T cells, had stronger expression on CD4 T cells from PMW by FACS (P < 0.04). Measurement of fragmentation of DAPI-binding nuclear proteins showed that CD4 T cells from PMW induce significant human umbilical vein endothelial cells (HUVEC) apoptosis compared to those from NC (P < 0.001). Furthermore, CD4 T cells from PMW expressed strong p-selectin glycoprotein ligand-1(PSGL-1) and integrin (CD18) but not L-selectin by FACS (P < 0.006, P < 0.05, n.s., respectively). Estrogen levels correlated negatively with PSGL-1 (R = 0.997, P < 0.05) and CD4 T cell-induced HUVEC apoptosis (R = 0.439, P < 0.0001). Treatment with 17β-estradiol showed reduction of CD4 T cell-induced apoptosis in PMW. Estrogen receptor antagonist ICI 172,780 abolished estrogen protection. Conclusions : From these results, we concluded that CD4 T cells in perimenopausal women were already activated and displayed dysfunctions related to deficiency of estrogen and estrogen receptors, which may be a factor that contributes to the acceleration of plaque erosion in atherosclerotic plaque and acute coronary syndromes.

scholarly journals Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion

2021 ◽  
Vol 7 (18) ◽  
pp. eabd2710
Author(s):  
Chen Zhu ◽  
Karen O. Dixon ◽  
Kathleen Newcomer ◽  
Guangxiang Gu ◽  
Sheng Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adaptor Protein ◽  
Transcriptional Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Autoreactive T Cell ◽  
Autoimmune Conditions ◽  
T Cell Dysfunction

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell–mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3−/− T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.

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