NIH grant: Differentiation, fate, and function of pathogenic T helper cells in graft-versus-host disease (1R01AI196441-01)

retained text

NIH grant 1R01AI196441-01: Differentiation, fate, and function of pathogenic T helper cells in graft-versus-host disease
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Matthew R Olson. Award: $775740.
Start: 2026-06-24T00:00:00.
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.

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