During chronic viral infections, T cells are exhausted due to constant antigen exposure and are associated with enhanced programmed death 1 (PD-1) expression. Deficiencies in the PD-1/programmed death-ligand 1 (PD-L1) pathway are associated with autoimmune diseases, including those of the central nervous system (CNS). To understand the role of PD-1 expression in regulating T-cell immunity in the CNS during chronic infection, we characterized PD-1 expression in cerebrospinal fluid (CSF) and blood of individuals with chronic human immunodeficiency virus type 1 (HIV-1) infection. PD-1 expression was higher on HIV-specific CD8
+ T cells than on total CD8
+ T cells in both CSF and blood. PD-1 expression on CSF T cells correlated positively with CSF HIV-1 RNA and inversely with blood CD4
+ T-cell counts, suggesting that HIV-1 infection drives higher PD-1 expression on CSF T cells. However, in every HIV-positive individual, PD-1 expression was higher on T cells in CSF than on those in blood, despite HIV-1 RNA levels being lower. Among healthy HIV-negative controls, PD-1 expression was higher in CSF than in blood. Furthermore, frequencies of the senescence marker CD57 were lower on CSF T cells than on blood T cells, consistent with our prior observation of enhanced ex vivo functional capacity of CSF T cells. The higher PD-1 expression level on CSF T cells therefore does not reflect cellular exhaustion but may be a mechanism to downregulate immune-mediated tissue damage in the CNS. As inhibition of the PD-1/PD-L1 pathway is pursued as a therapeutic option for viral infections, potential effects of such a blockade on development of autoimmune responses in the CNS should be considered.Programmed death 1 (PD-1; also called CD279) and its ligands, PD-L1 (also called B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD-273), regulate T-cell activation, peripheral tolerance, and autoimmunity (
22,
43). PD-1 can be expressed on CD8
+ and CD4
+ T cells, B cells, natural killer T cells, and activated monocytes. PD-L1 is expressed on various cells, including T and B cells, dendritic cells, macrophages, mast cells, nonhematopoietic cell types (including vascular endothelial cells, pancreatic islet cells, astrocytes, keratinocytes, and microglial cells), and cells in immune privileged sites, including the placenta and the eye (
22). PD-L2 expression is inducible and is restricted to dendritic cells, monocytes, macrophages, and mast cells (
22). During chronic infections, the PD-1/PD-L1 pathway inhibits antigen-specific T-cell responses (
7,
8,
35,
46). In human immunodeficiency virus type 1 (HIV-1)-infected individuals, PD-1 expression on HIV-specific T cells in peripheral blood is upregulated and correlates positively with plasma viremia and inversely with CD4
+ T-cell counts (
7,
46). PD-1 expression on HIV-specific T cells is also associated with T-cell exhaustion, as defined by a reduced ability to proliferate and produce cytokines (
7,
46). Inhibition of the PD-1/PD-L1 pathway augments HIV-specific CD8
+ and CD4
+ T-cell function, and antiretroviral therapy is associated with a significant reduction of PD-1 expression on HIV-specific T cells in peripheral blood (
8).The PD-1/PD-L1 pathway also limits immune-mediated tissue damage that may be caused by overreactive peripheral T cells, especially in immune privileged sites such as the central nervous system (CNS). In 1999, the importance of PD-1 for peripheral tolerance was first suggested by studies which showed that PD1
−/− mice develop lupus-like autoimmune diseases (
32). In humans, polymorphisms in the
PDCD1 gene, which encodes PD-1, have been associated with autoimmune diseases, including lupus, diabetes, rheumatoid arthritis, and multiple sclerosis (
20,
21,
25). Upregulation of PD-L1 in multiple sclerosis lesions from human brain tissue suggests a role for the PD-1/PD-L1 pathway in regulating T-cell activation and controlling immunopathological damage (
33).The CNS is involved by HIV-1 early during primary infection (
6,
13), and approximately 40% of patients who develop advanced AIDS without receiving antiretroviral therapy develop cognitive impairment (
6,
13,
38). While HIV-1 proteins gp120 (
3,
16) and Tat (
30) are directly neurotoxic and may contribute to HIV-associated dementia, detrimental neuropathogenic effects have also been postulated for inflammatory and innate immune cells, especially monocytes/macrophages and T cells (
11,
19,
49,
50). Immune responses cause neuropathogenesis during other viral infections, and cytotoxic T lymphocytes can worsen the disease through direct cytotoxicity or release of inflammatory cytokines such as gamma interferon (IFN-γ) (
14). However, we recently described higher frequencies of functional HIV-specific CD8
+ T cells in cerebrospinal fluid (CSF) than in blood among asymptomatic HIV-positive individuals with little or no HIV-1 RNA in CSF, suggesting that HIV-1-specific CD8
+ T cells help to control intrathecal viral replication (
40).To understand the role of the PD-1/PD-L1 pathway in regulating T-cell responses during viral infection of the CNS, we characterized PD-1 expression on T cells in CSF and peripheral blood among asymptomatic HIV-positive individuals. We hypothesized that T-cell PD1 expression would be lower in CSF than in blood, since HIV-1 RNA concentrations are lower in CSF than in plasma and the magnitude and breadth of IFN-γ-secreting HIV-specific T cells are greater in CSF than in blood (
40). We show that, in CSF, HIV-1 RNA correlates directly with PD-1 expression on CD4
+, CD8
+, and HIV-specific CD8
+ T cells. Unexpectedly, PD-1 expression on all T cells is higher in CSF than in blood in HIV-positive patients and healthy HIV-negative controls. In contrast, expression of the senescence marker CD57 is lower in CSF than in blood. These data suggest that higher PD-1 expression on T cells in CSF may be a mechanism to regulate T-cell immunity in the CNS, rather than indicating T-cell exhaustion, and that this regulation is increased by HIV-1 replication.
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