Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that following each bladder infection, a highly T H 2 skewed immune response directed at bladder re-epithelization is observed with limited capacity to clear infection. Initiating this response is a distinct subset of CD301b + OX40L + dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate T H 2 cells. The bladder epithelial repair response is cumulative and aberrant, as after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.

Dendritic Epidermal T Cells (DETCs) are generated exclusively in the fetal thymus and maintained in the skin epithelium throughout postnatal life of the mouse. DETCs have restricted antigenic specificity due to their exclusive usage of a canonical TCR. Although the importance of the TCR in DETC development has been well established, the exact role of TCR signaling in DETC homeostasis and function remains incompletely defined. Here, we investigated TCR signaling in fully matured DETCs by lineage-restricted deletion of the Lat gene, an essential signaling molecule downstream of the TCR. We found that Lat deletion impaired TCR-dependent cytokine gene activation and the ability of DETC undergoing proliferative expansion. However, LAT-deficient DETCs were able to maintain long-term population homeostasis even though with reduced proliferation rate. Mice with Lat deletion in DETCs exhibited delayed wound healing accompanied by impaired clonal expansion within the wound area. Our study revealed differential requirements of TCR signaling in homeostatic maintenance of DETCs and in their effector function during wound healing.