Th1 and Th17 cells have an established role in protective immunity to Bordetella pertussis, but this evidence is based largely on peripheral T cells. There is emerging evidence that local tissue-resident memory T (T_RM) cells that accumulate in tissue following mucosal infection may be crucial for long-term immunity. In this study, we examined the role of respiratory CD4 T_RM cells in immunity to B. pertussis Natural immunity to B. pertussis induced by infection is considered long lasting and effective at preventing reinfection. Consistent with this, we found that convalescent mice rapidly cleared the bacteria after reinfection. Furthermore, CD4 T cells with a T_RM cell phenotype (CD44⁺CD62L^-CD69⁺ or CD44⁺CD62L^-CD69⁺CD103⁺) accumulated in the lungs of mice during infection with B. pertussis and significantly expanded through local proliferation following reinfection. These CD4 T_RM cells were B. pertussis specific and secreted IL-17 or IL-17 and IFN-γ. Treatment of mice with FTY720, which prevented migration of T and B cells from lymph nodes to the circulation, significantly exacerbated B. pertussis infection. This was associated with significantly reduced infiltration of central memory T cells and B cells into the lungs. However, the local expansion of T_RM cells and the associated rapid clearance of the secondary infection were not affected by treatment with FTY720 before rechallenge. Moreover, adoptive transfer of lung CD4 T_RM cells conferred protection in naive mice. Our findings reveal that Ag-specific CD4 T_RM cells play a critical role in adaptive immunity against reinfection and memory induced by natural infection with B. pertussis.

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