title: Enhanced PD-1 expression by T cells in cerebrospinal fluid does not reflect functional exhaustion during chronic human immunodeficiency virus type 1 infection.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
authors.forename: Shanmugalakshmi
authors.initials: S
authors.lastname: Sadagopal
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Lorey
authors.forename: Louise
authors.initials: L
authors.lastname: Barnett
authors.forename: Deborah
authors.initials: D
authors.lastname: Sutherland
authors.forename: Rebecca
authors.initials: R
authors.lastname: Basham
authors.forename: Husamettin
authors.initials: H
authors.lastname: Erdem
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D015703:Antigens, CD / Q000134:cerebrospinal fluid / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*; D001773:Blood Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018959:CD57 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D016022:Case-Control Studies; D016922:Cellular Senescence; D002490:Central Nervous System / Q000276:immunology; D002555:Cerebrospinal Fluid / Q000276:immunology; D002908:Chronic Disease; D005786:Gene Expression Regulation / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral / Q000032:analysis; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018959:CD57 Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral