Age but not sex modifies lymphoid immune responses in murine sepsis

Sepsis disproportionately affects the elderly, and the cellular mechanisms driving age- and sex-dependent lymphoid immune remodeling remain poorly defined. In this work, we mapped the splenic lymphoid transcriptional landscape of young and older adult, male and female mice after sepsis by single-cell RNA sequencing. While both sexual and age dimorphism shaped the baseline lymphocyte composition, the transcriptional reprogramming induced by sepsis was significantly influenced only by age. Sepsis induced a proportional reduction in lymphocytes across age and sex groups; however, aging modified the pattern of lymphocyte reconstitution. Following sepsis, older adult mice displayed an enhanced B cell maturation compared to young mice. Moreover, across all major lymphocyte subtypes, older adult mice demonstrated transcriptionally suppressed metabolic pathways at baseline that shifted to exaggerated activation after sepsis. Furthermore, intercellular communication analysis from antigen-presenting cells to T cells revealed broadly age-dependent activation of co-stimulatory and antigen-presentation pathways after sepsis. Age and sepsis also widely reshaped the druggable landscape in lymphocytes, revealing a distinct predicted drug response profile in older adult mice after sepsis. These data suggest that aging reshapes the lymphoid baseline and the subsequent septic response in ways that may contribute to the poorer outcomes observed in older hosts. Notably, under these conditions, we did not detect significant sexual dimorphism. This lymphoid-specific age-driven transcriptional override highlights specific metabolic and signaling checkpoints as potential targets for precision immunotherapy in older sepsis.