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 (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 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 T EM durability, uncovering a spleen-centered protective mechanism with implications for improved TB vaccines and therapies.