Investigating donor CD8+ T cell differentiation post-experimental aHSCT in GVHD target tissues 3639

Abstract Description The onset of graft-vs-host-disease (GVHD) remains a major complication limiting the application of allogeneic hematopoietic stem cell transplantation (aHSCT) as a form of treatment for hematological malignancies. GVHD affects 30-60% of aHSCT patients, and accounts for 15% of deaths post-aHSCT. Following an aHSCT, recipient alloantigens provide the source of donor T cell activation. Although these interactions involving CD8+ T cells are beneficial for the anti-tumor Graft-vs-Leukemia (GVL) effect, the unwanted attack of healthy tissues (ex. liver, GI) result in GVHD. Post-aHSCT, donor alloreactive T cells undergo unyielding TCR stimulation. In cancer and chronic infections, this results in the gradual deterioration of T cell responses into the state of T cell exhaustion (TEX). A few studies have examined CD8+ TEX in GVHD, primarily in hematolymphoid compartments. However, whether CD8+ T cells differentiate into prototypic TEX, and their role in GVHD remains unclear. Our initial results of donor alloreactive CD8+ T cells post-aHSCT in several preclinical aHSCT murine models suggest a phenotype of decreased memory with increased co-expression of inhibitory markers within acute and chronic GVHD target tissues. Analyses of CD8+ T cells in clinical aHSCT samples also support our working hypothesis that persistent alloantigen stimulation drives CD8+ TEX. The elucidation of the differentiation fate of donor alloreactive CD8+ T cells post-aHSCT may enable therapeutic advances. Funding Sources NIH/NEI R01 Diversity Supplement Award: 08/01/2022 - 02/29/2024 T32 Translational Immunology Award: 08/01/2024 - 07/31/2025 Topic Categories Transplantation Immunology (TRAN)