Differentiation, fate, and function of pathogenic T helper cells in graft-versus-host disease

About This Grant

Project Summary/Abstract Graft-versus-host disease (GVHD) occurs in ~30-70% of individuals receiving hematopoietic cell transfer (HCT) cancer immunotherapy, significantly impacting treatment safety, efficacy, and patient quality of life. Intestinal inflammation is a key feature of GVHD in HCT recipients, characterized by the recruitment of CD4 T helper (Th) cells to the gut that promote tissue damage and inflammation. Current treatments for intestinal GVHD are only partially effective and can limit potent anti-cancer immunity. Thus, there is a need to better understand how pathogenic T cells arise post-HCT and how they can be targeted to reduce intestinal disease without impairing beneficial anti-cancer effects. To this end, we have identified a novel Th cell population that produces the serine protease granzyme A (GrA) in the inflamed intestines of mice and humans with immunotherapy-induced colitis. In mouse models, deletion of Th cell GrA eliminates intestinal GVHD while enhancing or maintaining anti-cancer immunity. GrA+ Th cells are required for early intestinal damage and may serve as precursors to other inflammatory Th subtypes that exacerbate disease. The objective of this proposal is to better understand the environmental cues that govern the differentiation of GrA+ Th cells and their contribution to intestinal inflammation. This information will allow specific therapeutic targeting of these cells without impairing anti-cancer immunity. The central hypothesis is that multiple STAT-activating cytokines induce a STAT3-centric transcription factor network that drives the differentiation of GrA+ Th cells that induce intestinal damage and act as precursors to other inflammatory Th subtypes. Our aims will test this hypothesis in three parts. 1) We will identify signals that selectively promote pathogenic GrA+ Th cells but are dispensable for anti-cancer immunity using murine and humanized models of intestinal GVHD. 2) We will determine the fate or plasticity of GrA-producing Th cells after HCT utilizing novel GrA conditional deletion and lineage-tracing mice. Finally, 3) we will determine the function of GrA in driving intestinal disease in mice and humans using mice lacking key features of GrA activity and spatial transcriptomics of human intestinal biopsies. This work is significant as we have identified a novel subtype of Th cells involved in intestinal disease after HCT that may be targeted therapeutically to prevent GVHD while maintaining potent anti-cancer immunity. The proposed studies are highly innovative; conceptually, we have identified GrA+ Th cells as mediators of early intestinal damage and as precursors to other inflammatory Th cell subtypes that further exacerbate inflammation. Technically, we have developed a novel GrA-centric mouse toolkit to examine these processes and will utilize spatial transcriptomics to identify their roles in human disease. This work will impact cancer immunotherapy recipients by establishing GrA+ Th cells as key mediators of intestinal GVHD and determining how these cells differentiate and contribute to disease. Overall, our studies will identify key points of therapeutic intervention that will enhance the safety and efficacy of HCT therapy.