CD45 regulates GM-CSF, retinoic acid and T-cell homing in intestinal inflammation

CD45 is a leukocyte-specific tyrosine phosphatase important for T-cell development, and as a result, CD45^-/- mice have substantially reduced numbers of T cells. Here we show that, upon dextran sodium sulfate (DSS)-induced colitis, CD45^-/- mice have equivalent intestinal pathology and T-cell numbers in their colon as C57BL/6 mice and show enhanced weight loss. CD45^-/- mice have a greater percentage of α4β7⁺ T cells prior to and after colitis and an increased percentage of T cells producing inflammatory cytokines in the inflamed colon, suggesting that CD45^-/- effector T cells preferentially home to the intestine. In DSS-induced colitis in CD45RAG^-/- mice lacking an adaptive immune system, CD45 was required for optimal granulocyte-macrophage colony-stimulating factor (GM-CSF) and retinoic acid (RA) production by innate immune cells. Addition of CD45^+/+ T cells led to greater weight loss in the RAG^-/- mice compared with CD45RAG^-/- mice that correlated with reduced α4β7⁺ T cells and lower recruitment to the colon of CD45RAG^-/- mice in DSS-induced colitis. Addition of exogenous GM-CSF to CD45RAG^-/- mice rescued RA production, increased colonic T-cell numbers, and increased weight loss. This demonstrates opposing effects of CD45 in innate and adaptive immune cells in proinflammatory responses and the expression of the gut-homing molecule, α4β7.