AbstractAging people living with HIV (PWH) frequently manifest impaired antibody (Ab) responses to seasonal flu vaccination which has been attributed to ongoing inflammation and immune activation. We have recently reported a similar scenario in old simian immunodeficiency virus (SIV) infected rhesus macaques (RM) with controlled viremia and have been able to compensate for this deficiency by immunotherapy with interleukin (IL)‐21‐IgFc. To understand the underlying mechanisms of IL‐21‐induced immunomodulation leading to enhanced flu vaccine response in aging and SIV, we have investigated draining lymph node (LN) cells of IL‐21‐treated and ‐untreated animals at postvaccination. We observed IL‐21‐induced proliferation of flu‐specific LN memory CD4 T cells, expansion of B cells expressing IL‐21 receptor (IL‐21R), and modest expansion of T follicular helper cells (Tfh) co‐expressing T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) and DNAX accessory molecule (DNAM‐1). Transcriptional analysis of LN cells of IL‐21‐treated animals revealed significant inhibition of germinal center (GC) Tfh and B‐cell interferon signaling pathways along with enhanced B‐cell development and antigen presentation pathways. We conclude that IL‐21 treatment at the time of flu vaccination in aging SIV‐infected animals modulates the inductive LN GC activity, to reverse SIV‐associated LN Tfh and B‐cell dysfunction. IL‐21 is a potential candidate molecule for immunotherapy to enhance flu vaccine responses in aging PWH who have deficient antibody responses.