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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.

In inflammatory bowel disease (IBD), inflammation can occur beyond the intestine and spread systemically causing complications such as arthritis, cachexia, and anemia. Here, we determine the impact of CD45, a pan‐leukocyte marker and tyrosine phosphatase, on IBD. Using a mouse model of T cell transfer colitis, CD25−CD45RBhighCD4+ T cells were transferred into Rag1‐deficient mice (RAGKO) and CD45‐deficient RAGKO mice (CD45RAGKO). Weight loss and systemic wasting syndrome were delayed in CD45RAGKO mice compared to RAGKO mice, despite equivalent inflammation in the colon. CD45RAGKO mice had reduced serum levels of TNF‐α, and reduced TNF‐α production by splenic myeloid cells. CD45RAGKO mice also had increased numbers of erythroid progenitors in the spleen, which had previously been shown to be immunosuppressive. Adoptive transfer of these erythroid progenitors into RAGKO mice reduced their weight loss and TNF‐α expression by splenic red pulp macrophages. In vitro, erythroid cells suppressed TNF‐α expression in red pulp macrophages in a phagocytosis‐dependent manner. These findings show a novel role for erythroid progenitors in suppressing the pro‐inflammatory function of splenic macrophages and cachexia associated with IBD.