A Highly Polarized Th2 Bladder Response to Infection Promotes Epithelial Repair at the Expense of Preventing New Infections

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.