Bystander activation of Bordetella pertussis-induced nasal tissue-resident memory CD4 T cells confers heterologous immunity to Klebsiella pneumoniae

Abstract Tissue-resident memory CD4 T ($T_{RM}$) cells induced by infection with Bordetella pertussis persist in respiratory tissues and confer long-term protective immunity against re-infection. However, it is not clear how they are maintained in respiratory tissues. Here we demonstrate that B. pertussis-specific CD4 $T_{RM}$ cells produce IL-17A in response to in vitro stimulation with LPS or heat-killed Klebsiella pneumoniae (HKKP) in the presence of dendritic cells. Furthermore, IL-17A-secreting CD4 $T_{RM}$ cells expand in the lung and nasal tissue of B. pertussis convalescent mice following in vivo administration of LPS or HKKP. Bystander activation of CD4 $T_{RM}$ cells was suppressed by anti-IL-12p40, but not by anti-MHCII antibodies. Furthermore, purified respiratory tissue-resident, but not circulating, CD4 T cells from convalescent mice produced IL-17A following direct stimulation with IL-23 and IL-1$\beta$ or IL-18. Intranasal immunization of mice with a whole cell pertussis vaccine induced respiratory CD4 $T_{RM}$ cells that were re-activated following stimulation with K. pneumoniae. Furthermore, the nasal pertussis vaccine conferred protective immunity against B. pertussis but also attenuated infection with K. pneumoniae. Our findings demonstrate CD4 $T_{RM}$ cells induced by respiratory infection or vaccination can undergo bystander activation and confer heterologous immunity to an unrelated respiratory pathogen