Induction of ICOS+CXCR3+CXCR5+ TH Cells Correlates with Antibody Responses to Influenza Vaccination

Seasonal influenza vaccine protects 60 to 90% of healthy young adults from influenza infection. The immunological events that lead to the induction of protective antibody responses remain poorly understood in humans. We identified the type of CD4(+) T cells associated with protective antibody responses after seasonal influenza vaccinations. The administration of trivalent split-virus influenza vaccines induced a temporary increase of CD4(+) T cells expressing ICOS, which peaked at day 7, as did plasmablasts. The induction of ICOS was largely restricted to CD4(+) T cells co-expressing the chemokine receptors CXCR3 and CXCR5, a subpopulation of circulating memory T follicular helper cells. Up to 60% of these ICOS(+)CXCR3(+)CXCR5(+)CD4(+) T cells were specific for influenza antigens and expressed interleukin-2 (IL-2), IL-10, IL-21, and interferon-gamma upon antigen stimulation. The increase of ICOS(+)CXCR3(+)CXCR5(+)CD4(+) T cells in blood correlated with the increase of preexisting antibody titers, but not with the induction of primary antibody responses. Consistently, purified ICOS(+)CXCR3(+)CXCR5(+)CD4(+) T cells efficiently induced memory B cells, but not naive B cells, to differentiate into plasma cells that produce influenza-specific antibodies ex vivo. Thus, the emergence of blood ICOS(+)CXCR3(+)CXCR5(+)CD4(+) T cells correlates with the development of protective antibody responses generated by memory B cells upon seasonal influenza vaccination.