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

A 3-week delay in the onset of T cell immunity to Mycobacterium tuberculosis (Mtb) 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 (TEM) 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 TEM versus primary. Paradoxically, lower numbers correlated with faster bacterial clearance, due to enhanced trafficking of secondary TEM to the spleen, where they responded to antigen. Further, secondary TEM recruited dendritic cells, which accelerated bacterial translocation from the lung to the spleen. Treating mice with a threshold number of airway-derived secondary TEM significantly reduced Mtb burden in the lung and spleen. Notably, Mtb killing was expedited by at least 15 days. Repeated antigen encounter bypassed priming requirements and enhanced TEM durability, uncovering a spleen-centered protective mechanism with implications for improved TB vaccines and therapies.