Antigen-experienced airway CD8⁺ effector memory T cells promote a detour pathway for mycobacterial killing in the spleen.

Abstract

A 3-week delay in the onset of T cell immunity to <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection compromises lung bacterial control, resulting in tuberculosis (TB). Restoring T cell function is a priority. We identified how airway CD44⁺CD62L^-KLRG1⁺CD8⁺ effector memory T cells (T_EM) in the lung enhance mycobacterial clearance via the spleen. Unexpectedly, a secondary immune response following repeated exposure of mice to Bacille Calmette-Guérin generated lower numbers of T_EM versus primary. Paradoxically, lower numbers correlated with faster bacterial clearance, due to enhanced trafficking of secondary T_EM to the spleen, where they responded to antigen. Further, secondary T_EM recruited dendritic cells, which accelerated bacterial translocation from the lung to the spleen. Treating mice with a threshold number of airway-derived secondary T_EM significantly reduced <i>Mtb</i> burden in the lung and spleen. Notably, <i>Mtb</i> killing was expedited by at least 15 days. Repeated antigen encounter bypassed priming requirements and enhanced T_EM durability, uncovering a spleen-centered protective mechanism with implications for improved TB vaccines and therapies.