Inadequate T follicular cell help impairs B cell immunity during HIV infection

The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations(1-3). 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 responses and plasma cell generation in vitro. Our results suggest that deregulation of T-FH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on T-FH cells. These results demonstrate a role for T-FH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations.