Urothelial antigen-specific CD4(+) T cells function as direct effector cells and induce bladder autoimmune inflammation independent of CD8(+) T cells

The role of CD4(+) T cells in bladder autoimmune inflammation has not been identified due to the lack of a proper animal model. We investigated CD4(+) T cell responses to bladder urothelial ovalbumin (OVA), a model self-antigen (Ag), in transgenic URO-OVA mice. The expression of bladder urothelial OVA rendered mice unresponsive to OVA and resulted in quick clearance of Ag-specific CD4(+) T cells. Adoptive transfer of naïve OVA-specific CD4(+) T cells led to exogenous T cell proliferation, activation, and bladder infiltration but no inflammatory induction. In contrast, adoptive transfer of pre-activated OVA-specific CD4(+) T cells induced bladder inflammation. Studies further demonstrated that CD4(+) T cells induced bladder inflammation in URO-OVA mice depleted of CD8(+) T cells or deficient in the recombinase activating gene-1 (Rag-1(−/−)). These results indicate that urothelial Ag-specific CD4(+) T cells can function as direct effector cells to induce bladder autoimmune inflammation independent of CD8(+) T cells.