Sentinel IL-17A-producing resident memory gamma delta T cells orchestrate the response to secondary oral Lm infection

ROMAGNOLI PA; SHERIDAN BS; PHAM QM; LEFRANCOIS L; KHANNA KM

Farmington, CT

Simposio; MICROBIOME MEETS CANCER AND IMMUNOLOGY; 2015

The Jackson Laboratory for Genomic Medicine

Resident memory gamma delta T cells provide rapid protection in tissues by sensing infection and recruiting both innate and adaptive arms of the immune system. Here we used parabiosis and multi-photon dynamic microscopy to show that following oral Listeria monocytogenes (Lm) infection, the Lm-elicited Vgamma4+ gamma delta T cells represent a resident memory (Trm) population that unexpectedly reside in the mesenteric lymph nodes. Gene and protein expression analysis showed that although these cells were located in the lymph nodes the gamma delta Trms failed to express CD62L and CCR7. However, we detected the expression of CD69 (marker for residency), CXCR3 and CXCR6. By employing multi-photon microscopy using TCRdelta-H2B-egfp reporter mice we found gamma delta Trm cells in the mesenteric lymph nodes exhibited a strikingly static pattern of migration with high arrest coefficient. This pattern radically changed following secondary oral Lm infection where the responding gamma delta T cells moved rapidly.Furthermore, we discovered are markable mechanism by which gamma delta Trms provided early protection against re-challenge Lm infection. We show that gamma delta Trms are the main producers of IL-17A critical for bacterial clearance. Using confocal microscopy, we show that during secondary infection gamma delta Trm formed clusters with neutrophils and IL17RA+inflammatory monocytes surrounding Lm aggregates in the mesenteric lymph nodes.Antibody blocking studies showed that IL-17A and CXCR3 regulated the redistribution of gamma delta Trms and the formation of granulomatous clusters. Blocking both IL-17A and CXCR3 significantly impaired bacterial clearance. Our findings support an exciting new role for pathogen elicited resident memory gamma delta T cells in orchestrating protective immune responses for the clearance of intestinal pathogens.