CXCR3 Provides a Competitive Advantage for Retention of Mycobacterium tuberculosis-Specific Tissue-Resident Memory T...

Mycobacterium tuberculosis is a major human pathogen, and new vaccines are needed to prevent transmission. Mucosal vaccination may confer protection against M. tuberculosis by stimulating tissue-resident memory (T_RM) CD4⁺ T cells in the lungs. The chemokine receptor CXCR3 promotes lung recruitment of T cells, but its role in T_RM development is unknown. This study demonstrates the recombinant influenza A virus vaccine PR8.p25, expressing the immunodominant M. tuberculosis T cell epitope p25, induces CXCR3 expression on p25-specific CD4⁺ T cells in the lungs so that the majority of vaccine-induced CD4⁺ T_RM expresses CXCR3 at 6 weeks. However, CXCR3^-/- mice developed equivalent antigen-specific CD4⁺ T cell responses to wild-type (WT) mice following PR8.p25, and surprisingly retained more p25-specific CD4⁺ T_RM in the lungs than WT mice at 6 weeks. The adoptive transfer of CXCR3^-/- and WT P25 T cells into WT mice revealed that the initial recruitment of vaccine-induced CD4⁺ T cells into the lungs was independent of CXCR3, but by 6 weeks, CXCR3-deficient P25 T cells, and especially CXCR3^-/- T_RM, were significantly reduced compared to CXCR3-sufficient P25 T cells. Therefore, although CXCR3 was not essential for CD4⁺ T_RM recruitment or retention, it provided a competitive advantage for the induction of M. tuberculosis-specific CD4⁺ T_RM in the lungs following pulmonary immunization.