Enhanced PD-1 Expression by T Cells in Cerebrospinal Fluid Does Not Reflect Functional Exhaustion during Chronic Human Immunodeficiency Virus Type 1 Infection

Sadagopal, Shanmugalakshmi; Lorey, Shelly L.; Barnett, Louise; Sutherland, Deborah; Basham, Rebecca; Erdem, Husamettin; Kalams, Spyros A.; Haas, David W.

doi:10.1128/jvi.01181-09

Cited by 12 publications

(11 citation statements)

References 52 publications

(85 reference statements)

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“…Both senescent and exhausted CD8 T cells have poor proliferative potential, but it has been unclear whether senescence and exhaustion represented distinct or overlapping biological processes (3). Previous studies have indicated at least a partial lack of overlap in expression of markers associated with senescence and exhaustion, such as CD57 and PD-1 (5,11,33,36). While in some human studies PD-1 and KLRG1 were found on the same population of virus-specific CD8 T cells (8), in mouse models, when PD-1 expression is very high, KLRG1 expression is low (41).…”

Section: Discussionmentioning

confidence: 96%

Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection

Angelosanto

Blackburn

Crawford

et al. 2012

J Virol

242

246

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T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection. However, at earlier stages of chronic infection, these virus-specific CD8 T cells retained the potential to partially or fully revert to a memory differentiation program after transfer to infection-free mice. Conversely, effector CD8 T cells primed during acute infection were not protected from exhaustion if transferred to a chronic infection. We also tested whether memory and exhausted CD8 T cells arose from different subpopulations of effector CD8 T cells and found that only the KLRG1 lo memory precursor subset gave rise to exhausted CD8 T cells. Together, these studies demonstrate that CD8 T cell exhaustion is a progressive developmental process. Early during chronic infection, the fate of virus-specific CD8 T cells remains plastic, while later, exhausted CD8 T cells become fixed in their differentiation state. Moreover, exhausted CD8 T cells arise from the memory precursor and not the terminally differentiated subset of effector CD8 T cells. These studies have implications for our understanding of senescence versus exhaustion and for therapeutic interventions during chronic infection.

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Section: Discussionmentioning

confidence: 96%

Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection

Angelosanto

Blackburn

Crawford

et al. 2012

J Virol

242

246

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“…Several lines of evidence support the notion that PD‐1+ CD8 T lymphocytes are not intrinsically incompetent at migrating to the CNS or to other organ attacked by deleterious autoimmune responses. A greater number of HIV‐specific CD8 T cells were found to express PD‐1 in the cerebrospinal fluid compared with their peripheral blood counterparts in HIV patients (Sadagopal et al,2010). Analysis of most tissues from chronically infected mice with lymphochoriomeningitis virus illustrated that the brain contained the highest levels of PD‐1 compared with other organs (Blackburn et al,2010).…”

Section: Discussionmentioning

confidence: 99%

The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD‐L1 levels on CNS cells

Pittet

Newcombe²,

Antel

et al. 2011

Glia

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Central nervous system (CNS) cells locally modulate immune responses using numerous molecules that are not fully elucidated. Engagement of programmed death-1 (PD-1), expressed on activated T cells, by its ligands (PD-L1 or PD-L2) suppresses T-cell responses. Enhanced CNS PD-1 and PD-L1 expression has been documented in inflammatory murine models; however, human CNS data are still incomplete. We determined that human primary cultures of astrocytes, microglia, oligodendrocytes, or neurons expressed low or undetectable PD-L1 under basal conditions, but inflammatory cytokines significantly induced such expression, especially on astrocytes and microglia. Blocking PD-L1 expression in astrocytes using specific siRNA led to significantly increased CD8 T-cell responses (proliferation, cytokines, lytic enzyme). Thus, our results establish that inflamed human glial cells can express sufficient and functional PD-L1 to inhibit CD8 T cell responses. Extensive immunohistochemical analysis of postmortem brain tissues demonstrated a significantly greater PD-L1 expression in multiple sclerosis (MS) lesions compared with control tissues, which colocalized with astrocyte or microglia/macrophage cell markers. However, more than half of infiltrating CD8 T lymphocytes in MS lesions did not express PD-1, the cognate receptor. Thus, our results demonstrate that inflamed human CNS cells such as in MS lesions express significantly elevated PD-L1, providing a means to reduce CD8 T cell responses, but most of these infiltrating immune cells are devoid of PD-1 and thus insensitive to PD-L1/L2. Strategies aimed at inducing PD-1 on deleterious activated human CD8 T cells that are devoid of this receptor could provide therapeutic benefits since PD-L1 is already increased in the target organ.

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“…Previously, it was shown that the expression of PD-1 is drastically upregulated on the exhausted T cells and the administration of anti-PDL-1 antibodies restores the CD8 function during chronic lymphocytic choriomeningitis virus (LCMV) infection (20). However, T cells expressing elevated PD-1 levels in HIV-1 infection do not appear to be functionally exhausted (42). Furthermore, we have repeatedly demonstrated that T cells in the CNS of TMEV-infected resistant B6 mice vigorously function for cytolysis and IFN-␥ production (34), yet the majority (ϳ70%) of the T cells express PD-1, similar to functionally compromised T cells in the CNS of infected susceptible SJL mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Role of Interleukin-6 in the Expression of PD-1 and PDL-1 on Central Nervous System Cells following Infection with Theiler's Murine Encephalomyelitis Virus

Jin

Hou

Kang

et al. 2013

J Virol

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bInfection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) of susceptible mice results in an immune-mediated demyelinating disease which is considered a relevant viral model of human multiple sclerosis. We previously demonstrated that the expression of positive costimulatory molecules (CD40, CD80, and CD86) is higher on the microglia of TMEV-resistant C57BL/6 (B6) mice than the microglia of TMEV-susceptible SJL/J (SJL) mice. In this study, we analyzed the expression levels of the negative costimulatory molecules PD-1 and PDL-1 in the CNS of TMEV-infected SJL mice and B6 mice. Our results indicated that TMEV infection induces the expression of both PD-1 and PDL-1 on microglia and macrophages in the CNS but not in the periphery. The expression of PD-1 only on CNS-infiltrating macrophages and not on resident microglia was considerably higher (>4-fold) in TMEV-infected SJL mice than TMEV-infected B6 mice. We further demonstrated that interleukn-6 (IL-6) is necessary to induce the maximal expression of PDL-1 but not PD-1 after TMEV infection using IL-6-deficient mice and IL-6-transgenic mice in conjunction with recombinant IL-6. In addition, cells from type I interferon (IFN) receptor knockout mice failed to upregulate PD-1 and PDL-1 expression after TMEV infection in vitro, indicating that type I IFN signaling is associated with the upregulation. However, other IFN signaling may also participate in the upregulation. Taken together, these results strongly suggest that the expression of PD-1 and PDL-1 in the CNS is primarily upregulated following TMEV infection via type I IFN signaling and the maximal expression of PDL-1 additionally requires IL-6 signaling.

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Enhanced PD-1 Expression by T Cells in Cerebrospinal Fluid Does Not Reflect Functional Exhaustion during Chronic Human Immunodeficiency Virus Type 1 Infection

Cited by 12 publications

References 52 publications

Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection

Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection

The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD‐L1 levels on CNS cells

The Role of Interleukin-6 in the Expression of PD-1 and PDL-1 on Central Nervous System Cells following Infection with Theiler's Murine Encephalomyelitis Virus

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