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

A T cell subset that emerges in blood after seasonal influenza vaccinations correlates with the development of protective antibody responses. What Lies Beneath Although the seasonal flu vaccine, which can protect 60 to 90% of young healthy adults, has been in use for decades, we still know surprisingly little about how it actually induces protective antibody responses. This information is especially important to improve vaccination efficacy in populations that are more susceptible to infection such as the very young and the elderly. Now, Bentebibel et al. take us a step further into understanding what is required for protective antibody responses in humans. The authors identified a subset of CD4+ T cells that were associated with protective antibody responses after seasonal flu vaccination in humans. These cells expressed the costimulatory molecules ICOS as well as two chemokine receptors, CXCR3 and CXCR5, which identify these cells as circulating memory T follicular helper (TFH) cells. TFH cells traditionally are thought to reside in the B cell follicles and be instrumental for germinal center formation and subsequent memory antibody response. Indeed, these circulating cells were influenza antigen–specific, could induce memory B cells to differentiate into plasma cells, and correlated with specific antibody titer. Further studies that find ways to harness these cells could thus improve vaccine design. 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 coexpressing 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-γ 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 naïve 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.