Immunosuppressive drugs and anti-inflammatory biologics are used to treat moderate-to-severe ulcerative colitis. Unfortunately, many patients suffer untoward effects, do not achieve remission and/or eventually relapse. Using a mouse model of colitis triggered by a pathogen of mice, we identified the host surface molecule B7-H3 as a suppressor of colonic inflammation. B7-H3 is thought to dampen the immune response to antigens, including microbial antigens, by suppressing the proliferation of ‘pathogenic lymphocytes’ that drive disease. We postulate that a weakened B7-H3 pathway contributes to ulcerative colitis. We will test the concept that stimulating the B7-H3 pathway suppresses colonic inflammation in mice and in humans. In mice, we will test whether treatment with recombinant B7-H3 protects the colon from inflammation and tissue damage elicited by a microbial pathogen. Using colonic biopsies obtained from patients with ulcerative colitis, we will test whether low B7-H3 expression is associated with high numbers of pathogenic lymphocytes and severe disease, and whether addition of recombinant B7-H3 blocks the proliferation of pathogenic lymphocytes. If successful, the proposed work will lay the foundation for additional studies aimed at optimizing the means to engage the B7-H3 pathway in ulcerative colitis.