Effector T cells and their cytokines are key players in Inflammatory Bowel Disease (IBD). Current therapies targeting T cells can result in remission of IBD, but are not curative, and have significant side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which suppress T cell activation. MDSCs are expanded in patients with IBD and during the recovery phase of dextran sulfate (DSS)-induced colitis and in scid mice in which colitis is induced by administration of WT CD4+CD45RBhi T cells. Our preliminary data show that expansion of CD11b+Gr1+ MDSCs in the spleen, and lamina propria (LP) in three distinct mouse models of colitis (WASP/WIP DKO mice, DSS-treated mice and Rag1-/- recipients of naive T cells) was associated with STAT5 degradation in T cells residing in the spleen and LP. STAT5 was also degraded in peripheral blood T cells from patients with active colitis. T cells from DSS treated mice had decreased proliferation, but increased production of IL-17A in response to T cell receptor (TCR) ligation. Co-culture with CD11b+Gr1+ cells from mice with colitis, but not from WT controls, caused STAT5 cleavage in WT CD4+Foxp3- Teff cells, but not CD4+Foxp3+ Treg cells. It also caused decreased T cell proliferation that was partially reversed by STAT5 transduction, and increased the production of IL-17A. STAT5 cleavage in T cells from mice with DSS colitis was dependent on caspase-1. Preliminary data shows that T cells from caspase1-/- mice are less colitogenic than WT cells. We will test the hypothesis that expansion and activation of MDSCs in colitis causes caspase-1 dependent STAT5 cleavage in Teff cells, altering their response to TCR ligation, and thereby modulating the severity of the disease. We will also test the hypothesis that MDSCs in colitis trigger the NLRP3 inflammasome to activate caspase-1, which then cleaves STAT5 in T cells, thereby mediating MDSCs driven alteration of T cell function. Finally, we will test the hypothesis that MDSCs from patients with IBD cause STAT5 cleavage in human T cells and alter their function. The proposed studies may suggest novel strategies that aim to control T cell activation in IBD.
Inflammatory bowel disease (IBD) affects up to 1,400,000 Americans. In the vast majority of cases, the cause of IBD is not known. The available therapies for IBD are not curative and have significant side effects. We have found that a population of white cells, called myeloid-derived suppressor cells (MDSCs), is expanded in IBD patients and causes cleavage in T cells of STAT5, a molecule that plays a key role in T cell activation, as well as increased production of the cytokine IL-17A, which aggravates colitis. The STAT5 cleavage is mediated by the enzyme caspase-1. This is important, because T cells from caspase deficient mice, which cannot cleave STAT5, have reduced colitogenic activity. STAT5 was cleaved in the peripheral blood T cells from IBD patients with active colitis, but not in remission. We will test the hypothesis that STAT5 cleavage in T cells by MDSCs modulates the severity of colitis. The results obtained will have a direct impact on the treatment of patients wih IBD. This is because caspase-1 activity, which promotes T cell colitogenic activity, can be blocked by inhibitors.