Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS+ circulating memory T follicular-helper cells which is impaired by HIV infection

Dysfunction of T follicular-helper (T-FH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory T-FH (cmT(FH)) cells (CD4(+) CD45RA(-)CD27(+)CXCR5(+)PD-1(+)) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM(+) and IgG(+) memory B cells at D0. In HIV seronegative subjects, production of IgG1(+) and IgG2(+) ASCs was consistently associated with the frequency of ICOS+ cmT(FH) cells but not ICOS(-)cmT(FH) cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmT(FH) cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 Kantibodies at D28 also correlated with ICOS+ cmT(FH) cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmT(FH) cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that T-FH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.