Defining the role of antigen-specific T cell responses in nash

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Regents of the University of Colorado (University of Colorado-Denver) $791,520 on February 4, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to define the role of antigen-specific T cell responses in metabolic dysfunction-associated steatohepatitis (MASH) and characterize T cell clonal expansion in liver disease progression.

The research identifies the antigens recognized by clonally expanded T cells in MASH, determines whether shared stimulatory antigens exist between human and mouse disease models, and establishes the antigen-presenting cells that drive T cell clonal expansion and whether these T cells induce or suppress disease progression. The project will establish a foundation for identifying novel therapeutic targets in chronic liver disease, where current treatment options are limited to lifestyle modification and transplantation.

Performance runs through November 30, 2029, at Aurora, Colorado. The award is classified as a Project Grant under 45 CFR Part 75.

Sub-recipients on the award include the Regents of the University of Minnesota (Office of Sponsored Projects Administration) and Nova Southeastern University, Inc., both receiving sub-awards dated May 27, 2026, to deliver the same research scope under sub-award numbers R01DK141551-FY26.1337.004 and R01DK141551-FY26.1337.003, respectively.

Abstract

Chronic liver diseases are a collection of disorders that result in significant morbidity and mortality worldwide. The overwhelming burden of these diseases results in the liver being the second most transplanted organ. As a result of a dramatic rise in the incidence of obesity and alcohol consumption, the rate of liver transplantation continues to climb world-wide. Despite the significant impact of chronic liver disease on society, there are no effective therapies to ameliorate disease outside of lifestyle modification and liver transplantation. Thus, a more rigorous understanding of the mechanisms that drive the progression of chronic liver disease is required to identify novel targets for therapeutic intervention. Our previous publication demonstrated a significant accumulation of T lymphocytes in the liver of individuals with metabolic dysfunction-associated steatohepatitis (MASH)-induced cirrhosis. However, the precise role of T cells in the progression of MASH has yet to be firmly established. The preliminary studies presented in this application have identified a yet to be appreciated role for T cell activation and clonal expansion during MASH. In this application we demonstrate that T cell clonal expansion is a common event that correlates with fibrosis stage in both humans and mice with MASH. These are the first studies to identify T cell clonal expansion in the liver of humans and/or mice with MASH and link T cell activation and function with MASH pathology. However, the exact antigenic cause of T cell activation or if these T cells are inducing or suppressing disease progression is unknown. The studies in this application aim to answer these two fundamental questions by defining (1) the antigens recognized by clonally expanded T cells, (2) if there are shared stimulatory antigens between human and mouse disease, (3) the antigen presenting cell (APC) that drives T cell clonal expansion, and (4) if eliminating T cell clonal expansion through depletion of either clonally expanded T cells or the apcs presenting antigens to these T cells results in prevention and/or resolution of disease. Completion of these studies will provide a paradigm shift in our understanding of the pathogenesis of MASH and will generate the tools necessary to define the role of T cells in the progression of other chronic liver diseases.