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The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations^,,. We report here that even though there is an expansion of follicular helper T (T_FH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)⁺ germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1–PD-L1 interaction in regulating T_FH cell function. In fact, we show that engagement of PD-1 on T_FH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody …