Altered Cytokine‐Induced STAT3 and STAT5 Activation of Peripheral T Follicular Helper Cells Contributes to Vaccine‐Non‐Responsiveness in Aging and HIV

Previous studies from our lab identified functional defects in antigen-specific peripheral T follicular helper cells (pTfh), characterized by low IL-21 and high IL-2 production, contributing to non-responsiveness to the influenza vaccine in both aging and HIV. This study investigated how IL-21-induced STAT3 and IL-2-induced STAT5 activation in pTfh cells affects vaccine responses in aging people with HIV (PWH) and those without HIV (PWoH). Ninety participants, including young (Y, ≤ 40 years) and old (O, ≥ 65 years) PWoH (YPWoH, n = 23; OPWoH, n = 25) and virally suppressed PWH (YPWH, n = 19; OPWH, n = 23), received the seasonal quadrivalent influenza vaccine. Samples were collected at pre-vaccination (day 0) and at days 14 and 28 post-vaccination. Participants were classified as vaccine responders (VR) or non-responders (VNR) based on serum antibody titers against vaccine antigens using the hemagglutination inhibition assay. Phosphoflow cytometry was performed on pre-vaccination PBMCs stimulated with IL-21 or IL-2, and high-dimensional analysis was performed using OMIQ software. Peripheral Tfh cells of young individuals showed greater IL-21-induced STAT3, reduced IL-2-induced STAT5 activity, and a reduced frequency of IL-2R+ pTfh cells compared to older individuals. IL-21-induced STAT3 in naïve CD4+ T cells in young participants correlated with the frequency of pTfh cells. Among VNR, IL-2-induced STAT5 in pTfh cells inversely correlated with day 28 vaccine titers. Our findings emphasize the essential role of IL-21 and IL-2-induced STAT signaling in orchestrating the immune response to vaccination. As individuals age, IL-2-induced STAT5 signaling in pTfh increases, potentially hindering Tfh cell differentiation and function, which may result in weaker vaccine responses.