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

Anti-inflammatory Trained Immunity Mediated by Helminth Products Attenuates the Induction of T Cell-Mediated Autoimmune Disease

Recent studies have suggested that the innate immune system can display characteristics of immunological memory and this has been called “innate immune memory” or “trained immunity.” Certain fungal products have been shown to induce epigenetic imprinting on monocytes/macrophages that results in heightened inflammatory responses to subsequent stimuli. Here we report that innate immune cells can be trained to be more anti-inflammatory following exposure to products of a helminth pathogen. Macrophages trained in vitro with Fasciola hepatica total extract (FHTE) had enhanced IL-10 and IL-1RA, but reduced TNF production upon re-stimulation with FHTE or TLR ligands and this was reversed by inhibitors of DNA methylation. In contrast, macrophages trained with β-glucan or Bacillus Calmette–Guérin had enhanced TNF production upon re-stimulation with Pam3cys or LPS. Furthermore, FHTE-trained macrophages had enhanced expression of markers of alternative activated macrophages (AAM). Macrophages from mice treated with FHTE expressed markers of AAM and had heightened IL-10 and IL-1RA production in response to FHTE or TLR ligands and had suppressed TNF and IL-12p40 production. Macrophages from mice treated with FHTE had reduced APC function and inhibited IL-17 production and the encephalitogenic activity of T cells in the experimental autoimmune encephalomyelitis (EAE) model. In addition, mice pre-treated with FHTE were resistant to induction of EAE and this was associated with a significant reduction in IL-17-producing γδ and CD4 T cells infiltrating the CNS. Our findings reveal that cells of the innate immune system can be trained in vitro or in vivo to be more anti-inflammatory by exposure to helminth products and this protects mice against the induction of a T cell-mediated autoimmune disease

Immunization with whole cell but not acellular pertussis vaccines primes CD4 T <inf>RM</inf> cells that sustain protective immunity against nasal colonization with Bordetella pertussis

Protective immunity wanes rapidly after immunization of children with acellular pertussis (aP) vaccines and these vaccines do not prevent nasal colonization or transmission of Bordetella pertussis in baboons. In this study, we examined the role of tissue-resident memory T (TRM) cells in persistent protective immunity induced by infection or immunization with aP and whole-cell pertussis (wP) vaccines in mice. Immunization of mice with a wP vaccine protected against lung and nasal colonization, whereas an aP vaccine failed to protect in the nose. IL-17 and IFN-?-secreting CD69+CD4+ TRM cells were expanded in the lung and nasal tissue after B. pertussis challenge of mice immunized with wP, but not aP vaccines. However, previous infection induced the most persistent protection against nasal colonization and this correlated with potent induction of nasal tissue TRM cells, especially IL-17-secreting TRM cells. Blocking T cell migration to respiratory tissue during immunization with a wP vaccine impaired bacterial clearance, whereas transfer of TRM cells from convalescent or wP-immunized mice conferred protection to na?ve mice. Our findings reveal that previous infection or wP vaccination are significantly more effective than aP vaccination in conferring persistent protective immunity against B. pertussis and that this is mediated by respiratory TRM cell