Tissue-resident memory T cells mediate mucosal immunity to recurrent urinary tract infection

Urinary tract infection (UTI) is one of the most prevalent human bacterial infections. Due to the rapid rise of multidrug-resistant uropathogens in global circulation, new therapeutic approaches, including vaccination and immunotherapy, are urgently needed. However, the development of these therapies is impeded by an incomplete understanding of how memory develops during UTI. Here, we found that reducing bacteria load early in infection, by reducing the quantity of bacteria used for infection or with antibiotics, completely abrogated the protective memory response. As we observed that a mixed T helper cell polarization bias, comprised of Th1, Th2, and Th17 T cells, develops during a primary infection, we hypothesized that reducing antigen load altered T helper cell polarization. Surprisingly, T helper cell polarization was unchanged in these scenarios. However, we uncovered a population of tissue resident memory (TRM) T cells that was significantly reduced in the absence of sufficient antigen, demonstrating that this population is necessary for protection. Supporting that TRM T cells are sufficient to protect against recurrent infection, depletion of systemic T cells, or treatment with FTY720 to block migration of memory lymphocytes from lymph nodes to infected tissue, did not compromise the adaptive immune response to a second infection. Thus, our findings point to an unappreciated mechanism of adaptive immunity to UTI and key role for TRM cells in the memory response to bacterial infection in this mucosa, providing a target for non-antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI.