Barrier Immune Memory is Promoted by Intestinal Epithelial Cell Presentation of Injected Bacterial Antigens
The contributions of antigen compartmentalization to recognition differences between CD4 and CD8 T cells have long been appreciated, but little is known of how subcellular localization of different antigens expressed by a single pathogen impacts T cell immunity. By tracking a clonal CD4 T cell response to its cognate epitope shuttled between different virulence proteins of the enteropathogenic bacterium, Citrobacter rodentium (Cr), we find a remarkable bias in the magnitude and quality of the response contingent on whether antigen remains bacterially associated or is introduced into intestinal epithelial cells colonized by the bacterium. Only proteins injected into the cytosol of colonocytes via the type 3 secretion system (T3SS) of Cr were found to recruit robust antigen-specific T cell responses to the infected mucosa and give rise to CD4 resident memory T (Trm) cells that populate the mucosal epithelium--and this required direct presentation of these antigens by infected epithelial cells. Single-cell transcriptomic analyses revealed that sustained, bidirectional epithelial-T cell communication was required both to elicit epithelial barrier-protective T cell help and to promote transcriptional networks that program a tissue-residency rather than central memory fate. These results establish a central role for antigen presentation by non-professional APCs in controlling memory fate decisions by CD4 T cells, with important implications for development of successful mucosal vaccines.