title: Responsiveness of HIV-specific CD4 T cells to PD-1 blockade.
abstract: Defining the T helper functions impaired by programmed death-1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-γ), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD-1high sorted CD4 T-cell subsets. Compared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Filippos
authors.initials: F
authors.lastname: Porichis
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kwon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zupkosky
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Tighe
authors.forename: Ashley
authors.initials: A
authors.lastname: McMullen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: David F
authors.initials: DF
authors.lastname: Pavlik
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez-Garcia
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kavanagh
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D061026:Programmed Cell Death 1 Receptor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor