Role of Myeloid Derived Suppressor Cells in intestinal inflammation

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DESCRIPTION (provided by applicant): 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.