UC San Diego

Inflammatory bowel disease (IBD) is a complicated disease characterized by an inflammation of the gastrointestinal (GI) tract, but the mechanism remains unknown. Among all the immune cells, T cells showed strong association with IBD pathogenesis. In this thesis, we studied how T cells contribute to IBD through genetics and pathogenic transcriptomic programs. Genome wide association studies (GWAS) identify a site near the metabolism gene laccase domain containing 1 (LACC1) as a risk for Crohn’s disease (CD). We previously found in populations that the Crohn’s disease risk allele correlates with decreased LACC1 expression in T lymphocytes. Despite this, the mechanism by which T cell gene expression is affected, and a link to T cell function and inflammatory disease, remained unknown. Here we identified sites in the promoter region in a haploblock that influenced LACC1 gene expression. Direct association of disease-risk variants with lower LACC1 mRNA was confirmed by comparing transcript quantity of the alleles in LACC1 heterozygous human CD4+ T cells. Using gene editing, we validated the role of this LACC1 region in gene expression in T cells. Human CD4+ T cells with LACC1 gene knockdown showed altered metabolism and reduced regulatory T cell differentiation. Overall, our study connects a disease GWAS hit by linking promoter region alterations specifically to changes in T cell metabolism and function. In the other part of the thesis, to identify the pathogenic T cell subsets, we compared T cells from the inflamed and non-involved tissues of active UC patients, with T cells from healthy donors and remission patients whose UC symptoms were temporarily suppressed by medications. Single-cell RNA seq analysis indicated that CD4 and CD8 T cells from inflamed tissues both showed increased IL17A-expressing cells (TH17/TC17), and TCF7-expressing stem-like T cells, which all showed more activation and pro-inflammatory features. RNA velocity and TCR analyses implied that the pathogenic TH17/TC17 cells subsets were derived from TCF7-expressing stem-like T cells, thus we hypothesized that stemness program is critical for the disease development. To validate the idea, we adaptively transferred Bcl6-deficient T cells, whose stemness program was impaired, into Rag1-/- mice to induce colitis. Compared to WT T cells, Bcl6-deficient T cells induced much less severe colitis with lower expansion and lower pathogenic TH17/TC17 populations, which showed high TFH gene signatures. In summary, our study unveiled the novel stem-like T cells in colitis, which could lead to new therapies to the disease.