CD94/NKG2A-Qa-1b Axis as a Key Modulator of Vaccine Responsiveness in Aging Populations

Vaccine responses decline with age, yet underlying mechanisms remain unclear. Using an Alum-adjuvanted spike (S+Alum) vaccine, this study identifies an aging-linked pathway in which senescence-associated secretory phenotype cytokines (CCL2, IL-6, IFN-γ) at the injection site are upregulated and associate with increased H2-T23 (Qa-1b) expression on monocytes. These H2-T23high monocytes interact with MHCIIhigh cDC2 via IL-10/TGF-β, limiting dendritic-cell antigen presentation, and engage the CD94/NKG2A-Qa-1b 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-1b 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.