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

Abstract

Urinary tract infection (UTI) is one of the most prevalent human bacterial infections. New therapeutic approaches, including vaccination and immunotherapy, are urgently needed to combat the rapid global dissemination of multidrug-resistant uropathogens. Development of therapies is impeded by an incomplete understanding of memory development during UTI. Here, we found that reducing bacterial load early in infection, by reducing the inoculum or with antibiotics after infection, completely abrogated the protective memory response. We observed a mixed T helper (T H ) cell polarization, composed of T H 1, T H 2, and T H 17 T cells, among T cells infiltrating the bladder during primary infection. Thus, we hypothesized that reducing antigen load altered T H cell polarization, leading to poor memory. Unexpectedly, however, T H cell polarization was unchanged in these scenarios. Instead, we uncovered a population of tissue-resident memory (T RM ) T cells that was significantly reduced in the absence of sufficient antigen. Demonstrating that T RM cells are necessary for immune memory, transfer of lymph node– or spleen-derived infection-experienced T cells to naïve animals did not confer protection against infection. Supporting that T RM cells are sufficient to protect against recurrent UTI, animals depleted of systemic T cells, or treated with FTY720 to block memory lymphocyte migration from lymph nodes to infected tissue, were equally protected compared with unmanipulated mice against a second UTI. Thus, we uncovered an unappreciated key role for T RM cells in the memory response to bacterial infection in the bladder mucosa, providing a target for non–antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI.

Vaccines against extraintestinal pathogenic Escherichia coli (ExPEC): progress and challenges

“…A recent study showed that, in a mouse model of recurrent UTI, bladder tissue-resident memory T cells (T rm ) are both necessary and sufficient for developing immune memory. 120 Interestingly, the authors found no T H subset cell skewing among CD 4 + T cells in bladder and draining lymph nodes post infection. Instead, a mixture of T H 1, T H 2, T H 17, and T reg cells was detected over 7 days of infection.…”

“… 120 Additionally, mice that lack mature B cells achieved a level of bacterial clearance comparable to wild-type mice during reinfection, suggesting that B cells are dispensable for UTI memory. 120 Another mouse study also pointed out that T H 1 cells instead of serum IgG are responsible for the increased bacterial clearance induced by vaccination. 117 As most past vaccine studies have considered B cell antibody response as a hallmark for protection, these findings question the paradigm and highlight the protective role of T cells in immune memory.…”

“…Instead, a mixture of T H 1, T H 2, T H 17, and T reg cells was detected over 7 days of infection. 120 It remains unclear how each of these T H subsets participate in the formation of the T rm reservoir, an area worth future investigation. 120 Additionally, mice that lack mature B cells achieved a level of bacterial clearance comparable to wild-type mice during reinfection, suggesting that B cells are dispensable for UTI memory.…”

“… 120 It remains unclear how each of these T H subsets participate in the formation of the T rm reservoir, an area worth future investigation. 120 Additionally, mice that lack mature B cells achieved a level of bacterial clearance comparable to wild-type mice during reinfection, suggesting that B cells are dispensable for UTI memory. 120 Another mouse study also pointed out that T H 1 cells instead of serum IgG are responsible for the increased bacterial clearance induced by vaccination.…”

“… 117 As most past vaccine studies have considered B cell antibody response as a hallmark for protection, these findings question the paradigm and highlight the protective role of T cells in immune memory. Although it remains unknown how vaccine immune response can be programmed toward the production of T rm cells, 120 more research on cellular memory response will provide insights into a better vaccine design.…”