Investigating the tissue location and protective function of oral vaccine-specific tissue resident memory CD4 T cells

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Abstract Vaccination is our most important preventative therapy against infectious disease. Protective immunity at mucosal sites has the potential to prevent re-infection by stopping invasion of the host. The small intestinal mucosa is amongst the most common sites of infection, but the mechanisms of vaccine-induced immune- mediated protection at this site remain relatively unknown. The primary target of an effective vaccine is the creation of long-lived B cells and T cells that provide durable protection. How CD4+ T cells might contribute to vaccine-mediated protection is unclear. We have developed a model of oral vaccination with an attenuated version of the E. coli heat labile toxin (LT) that induces large populations of vaccine-specific CD4+ T cells that are necessary for protection against re-infection. Using MHC class II tetramers we demonstrated that oral vaccination induces a long-lived population of LT-specific intestinal memory CD4+ T cells share a transcriptomic signature with Tissue-resident memory T cells (Trms). LT-specific T cells also expressed genes associated with enteric nerve function and after vaccination CD4+ T cells were observed adjacent to enteric nerves. Our hypothesis is that oral vaccine-specific CD4+ Trms protect the intestine by interacting with nerves to activate motility and physically expel enteric pathogens upon re-encountering their antigen. To test this question we need to develop a novel T cell receptor (TCR) transgenic mouse, specific to a dominant MHC class II-restricted antigen from LT. Via adoptive transfer of LT-specific TCR transgenic memory T cells we can test the hypothesis that these cells are sufficient to mediate protection against enteric infection. Further, LT- specific TCR transgenic T cells can be easily identified in tissues using congenic markers and we propose to use them to identify which nerves oral vaccine-activated CD4+ T cells interact with in the small intestine. At the conclusion of this grant we will have developed a first in its kind TCR transgenic mouse that will drastically increase our ability to make important discoveries about the biology and protective effects of CD4+ Trms in the small intestine, but also will undoubtedly be of use to the scientific community interested in oral vaccines.