Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection

Shankar, Premlata; Russo, Melissa L.; Harnisch, Brooke; Patterson, P. Daniel; Skolnik, Paul R.; Lieberman, Judy

doi:10.1182/blood.v96.9.3094.h8003094_3094_3101

Cited by 136 publications

(80 citation statements)

References 57 publications

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“…In case of chronic virus infections, cancers (194) and persistent bacterial infections (195), continued in vivo exposure to high levels of antigen leads to severe dysfunction of CD8 T cells, also designated CD8 T cell exhaustion. Originally CD8 T cell exhaustion was described after chronic infection of mice with LCMV (196), but was also shown to occur after HCV (197) and HIV (198–202) infection of humans, SIV in rhesus macaques (203), polyomavirus (204), adenovirus (205), Friend retrovirus (206) and mouse hepatitis virus (207) infection of mice.…”

Section: ‘Memory’ During Chronic Productive Infectionmentioning

confidence: 99%

Virus‐specific CD8 T cells: activation, differentiation and memory formation

Wiesel

Walton

Richter

et al. 2009

APMIS

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Wiesel M, Walton S, Richter K, Oxenius A. Virus-specific CD8 T cells: activation, differentiation and memory formation. APMIS 2009; 117: 356-81. CD8 T cells are pivotal for the control of many intracellular pathogens, and besides their role in immediate control of infections, CD8 T cells have the capacity to differentiate into long-lived antigenindependent memory CD8 T cells, at least in situations of acute and resolved infections. The population of memory cells is heterogeneous with respect to their phenotype, their anatomical localization and their functional capacities in order to afford optimal protection against secondary infections. In the past years, it has become clear that multiple in vivo parameters are involved in shaping the composition of the memory CD8 T cell population, including antigen load, duration and strength of CD8 T cell stimulation, the level of inflammation, availability of CD4 T cell help and CD8 T cell precursor frequencies. With respect to the timing when CD8 T cells are committed to become memory cells, several models have been proposed. In contrast to acute, resolved infection, the continued in vivo exposure to high levels of antigen during persistent chronic viral infection precludes the development of long-lived antigen-independent memory CD8 T cells and might even result in severe dysfunction of virus-specific CD8 T cells.

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Section: ‘Memory’ During Chronic Productive Infectionmentioning

confidence: 99%

Virus‐specific CD8 T cells: activation, differentiation and memory formation

Wiesel

Walton

Richter

et al. 2009

APMIS

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“…Attenuation of viral‐specific T‐cell responses in chronic viral infections has been related to a phenomenon known as T‐cell exhaustion 10, 11. In recent years, T‐cell exhaustion in persistent viral infections has been emphasized to be modulated through the “programmed death‐1” (PD‐1) signaling pathway 12, 13.…”

Section: Introductionmentioning

confidence: 99%

HCV‐specific T cells in HCV/HIV co‐infection show elevated frequencies of dual Tim‐3/PD‐1 expression that correlate with liver disease progression

et al. 2010

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Co-infection of HCV with HIV has been associated with more rapid progression of HCV-related disease. HCV-specific T-cell immune responses, which are essential for disease control, are attenuated in co-infection with HIV. T-cell exhaustion has recently been implicated in the deficient control of chronic viral infections. In the current study, we investigated the role of programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) expression in T-cell exhaustion during HCV/HIV co-infection. We show that in HCV/HIV co-infection, both total and HCV-specific T cells co-express Tim-3 and PD-1 in significantly higher frequencies, compared with HCV mono-infection. Co-expression of these two markers on HCV-specific CD8 1 T cells positively correlated with a clinical parameter of liver disease progression. HCV-specific CD8 1 T cells showed greater frequencies of Tim-3/PD-1 co-expression than HIV-specific CD8 1 T cells, which may indicate a greater degree of exhaustion in the former. Blocking Tim-3 or PD-1 pathways restored both HIV-and HCV-specific CD8 1 T-cell expansion in the blood of co-infected individuals. These data demonstrate that co-expression of Tim-3 and PD-1 may play a significant role in HCV-specific T-cell dysfunction, especially in the setting of HIV co-infection.

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“…Adoptive transfer experiments revealed that a large fraction of specific CTL disappeared from the circulation and from the lymphoid organs. This process has also been documented for chronic viral infections, and is referred to as exhaustion 19, 21–26. The phenotype of CTL that resist physical deletion in the presence of a chronic infection has been analyzed before.…”

Section: Discussionmentioning

confidence: 99%

Chronic myelogenous leukemia maintains specific CD8⁺ T cells through IL‐7 signaling

et al. 2010

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Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease of hematopoietic stem cells. The disease progresses after several years from an initial chronic phase to a blast phase. Leukemia-specific T cells are regularly detected in CML patients and may be involved in the immunological control of the disease. Here, we analyzed the role of leukemia-specific CD81 T cells in CML disease control and the mechanism that maintains CD8 1 T-cell immunosurveillance in a retroviral-induced murine CML model. To study antigen-specific immune responses, the glycoprotein of the lymphocytic choriomeningitis virus was used as model leukemia antigen. Leukemiaspecific CTL activity was detectable in vivo in CML mice and depletion of CD8 1 T cells rapidly led to disease progression. CML-specific CTL were characterized by the expression of the IL-7 receptor a-chain. In addition, leukemia cells produced IL-7 that was crucial for the maintenance of leukemia-specific CTL and for disease control. Therefore, CML cells maintain the specific CD8 1 T-cell-mediated immune control by IL-7 secretion. This results in prolonged control of disease and probably contributes to the characteristic chronic phase of the disease.Key words: CD8 1 T cells . Chronic myelogenous leukemia . IL-7 signaling Supporting Information available online IntroductionChronic myelogenous leukemia (CML) is a malignant clonal disease originating from a pluripotent hematopoietic stem cell expressing the reciprocal translocation t(9;22), which forms the oncogenic BCR/ABL fusion protein. BCR/ABL is a constitutively activated tyrosine kinase which plays a critical role in the pathogenesis of CML. After several years and acquisition of a second genetic abnormality, the disease progresses from the chronic phase to terminal blast phase in which the patients develop an acute leukemia of either myeloid (AML) or, less frequent, lymphoid (ALL) cell type [1][2][3]. For unknown reasons, CML seems to be the most immunogenic leukemia. Experiences from stem cell transplantations (SCT) suggest that T cells play an important role in the immunological control of CML. After allogeneic SCT, recipients of T-cell-depleted grafts have a higher incidence of relapses, and post-transplant relapses can be restored to permanent molecular remissions by donor lymphocyte infusions [4,5]. In addition, specific CTL recognizing leukemia antigens such as BCR/ABL, proteinase-3 and Wilms tumor 1 protein have been identified in CML patients without SCT [6]. However, in the peripheral blood Ã These authors have contributed equally to this work. 2720of CML patients, only low-avidity CTL were detectable. Highavidity CTL might have been deleted through apoptotic processes due to the persistence of the CML [7]. Nevertheless, CML-specific CTL may be involved in the control of the leukemia in the chronic phase over several years and coexist with the leukemia. The mechanisms controlling this delicate balance between the immune system and leukemia are largely unknown. CD8 1 T cells are activated and dev...

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Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection

Cited by 136 publications

References 57 publications

Virus‐specific CD8 T cells: activation, differentiation and memory formation

Virus‐specific CD8 T cells: activation, differentiation and memory formation

HCV‐specific T cells in HCV/HIV co‐infection show elevated frequencies of dual Tim‐3/PD‐1 expression that correlate with liver disease progression

Chronic myelogenous leukemia maintains specific CD8⁺ T cells through IL‐7 signaling

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Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection

Cited by 136 publications

References 57 publications

Virus‐specific CD8 T cells: activation, differentiation and memory formation

Virus‐specific CD8 T cells: activation, differentiation and memory formation

HCV‐specific T cells in HCV/HIV co‐infection show elevated frequencies of dual Tim‐3/PD‐1 expression that correlate with liver disease progression

Chronic myelogenous leukemia maintains specific CD8+ T cells through IL‐7 signaling

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Chronic myelogenous leukemia maintains specific CD8⁺ T cells through IL‐7 signaling