Investigating the role of gzma-producing tissue-resident memory TH17 cells in inflammatory bowel disease

The National Institute of Allergy and Infectious Diseases awarded the University of Southern California $100,228 on December 4, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of granzyme-A-producing tissue-resident memory TH17 cells in inflammatory bowel disease.

The project examines a newly identified population of CD4 tissue-resident memory TH17 cells that express granzyme A, a cytotoxic effector molecule typically associated with CD8 T cells and natural killer cells. Preliminary data from human IBD tissues reveal granzyme A is highly enriched in tissue-resident memory cells at sites of epithelial barrier loss. The research integrates antibody depletion, conditional knockout mice targeting granzyme A in CD103 tissue-resident memory cells, single-cell RNA sequencing, in vivo CRISPR screening, and genetic knockout validation to define the functional contribution of granzyme A to disease and identify transcriptional regulators. Outcomes will assess epithelial integrity, inflammation, and clinical disease severity to uncover potential therapeutic targets for Crohn's disease and ulcerative colitis.

Work is performed in Los Angeles, California. The period of performance runs from December 4, 2026, through June 7, 2029. The assistance type is a project grant.

Abstract

Inflammatory bowel disease (IBD), which includes crohn's disease and ulcerative colitis, affects more than 3 million individuals in the united states. IT is marked by relapsing intestinal inflammation, epithelial barrier dysfunction, and long-term tissue damage. Despite progress in immunosuppressive therapies, many patients remain refractory to treatment or experience recurrent flares, underscoring the urgent need for new mechanistic insights and targeted interventions. This proposal investigates a newly identified population of CD4⁺ tissue- resident memory TH17 (TRM17) cells that express granzyme a (gzma), a cytotoxic effector molecule typically associated with CD8⁺ t cells and NK cells. Preliminary data from human IBD tissues reveal that gzma is highly enriched in TRM cells at sites of epithelial barrier loss. In murine models of colitis, TRM17 cells exhibit selective gzma expression, distinguishing them from other t cell populations that express granzyme b or IFN-γ. These findings support a model in which TRM17-derived gzma drives epithelial damage and sustains chronic inflammation. Aim 1 will define the functional contribution of gzma to disease using antibody depletion and conditional knockout mice targeting gzma in CD103⁺ TRM cells. Aim 2 will identify transcriptional regulators of gzma using single-cell RNA sequencing and in vivo crispr screening, followed by validation in genetic knockout models. Outcomes will assess epithelial integrity, inflammation, and clinical disease severity. This project integrates advanced immunological techniques, spatial and single-cell transcriptomics, gene editing, and in vivo models to dissect a novel cytotoxic pathway in CD4⁺ t cells. IT is among the first to mechanistically explore the effector functions of TRM17 cells in IBD and could uncover new therapeutic targets. The findings may also provide broader insight into tissue-resident t cell behavior in other chronic inflammatory conditions. The applicant brings a unique interdisciplinary background in biomedical engineering and computational biology, which enhances his ability to bridge bench science with high-dimensional data analysis. Through this fellowship, the applicant will gain hands-on experience in flow cytometry, t cell functional assays, spatial transcriptomics, crispr screening, and colitis models. He will receive mentorship from a multidisciplinary team with expertise in mucosal immunology, t cell biology, and transcriptomic data interpretation. Training will be reinforced through formal coursework, workshops in scientific communication and grant writing, and peer mentoring activities. The MMI program at USC provides a highly collaborative, well-resourced environment for advanced graduate training. This fellowship will prepare the applicant for a successful academic career as an independent investigator focused on translational immunology and inflammatory disease.