CD94/NKG2A-Qa-1^b axis as a key modulator of vaccine responsiveness in aging populations

Vaccine responses decline with age, yet the underlying mechanisms remain unclear. Using an aluminum hydroxide (Alum)-adjuvanted spike (S+Alum) vaccine, this study identifies an aging-linked pathway in which senescence-associated secretory phenotype (SASP) cytokines (C-C motif chemokine ligand 2, interleukin [IL]-6, and interferon-γ) at the injection site are upregulated and associate with increased histocompatibility 2, T region locus 23 (H2-T23; Qa-1^b) expression on monocytes. These H2-T23^high monocytes interact with MHCII^high conventional type 2 dendritic cells via IL-10/transforming growth factor β, limiting dendritic cell antigen presentation, and engage the CD94/natural killer cell receptor group II number A (NKG2A)-Qa-1^b checkpoint on T cells, further dampening immunity. In humans, HLA-E⁺ monocytes and NKG2A⁺ T cells are infrequent in young individuals but show higher prevalence in peripheral blood from older adults, highlighting this pathway as a regulatory target. Blocking the CD94/NKG2A-Qa-1^b axis thus emerges as a potential strategy to enhance vaccine performance in aging populations. Overall, the findings define a mechanistic link between SASP-driven myeloid programming, impaired antigen presentation, and checkpoint-mediated T cell restraint in aging, with implications for vaccine design tailored to older individuals.