The molecular basis of T cell allorecognition in graft-versus-host-disease and graft-versus-leukemia

The National Institute of Allergy and Infectious Diseases awarded Massachusetts Institute of Technology $100,228 on November 7, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

MIT will conduct research examining the molecular basis of T cell allorecognition in graft-versus-host disease and graft-versus-leukemia. The research uses a repertoire-scale examination to determine the molecular mechanisms underlying T cell recognition of non-self major histocompatibility complexes after allogeneic hematopoietic stem cell transplantation. The work characterizes alloreactive T cell repertoires in both graft-versus-host disease and graft-versus-leukemia responses using a single MHC-mismatched bone marrow transplant and tumor model to study alloreactive T cell receptors against a single MHC.

Work is performed in Cambridge, Massachusetts. The period of performance extends from the award date through August 31, 2029.

Abstract

T cells play an integral role in defending hosts from pathogens and cancer through T cell receptor (TCR) recognition of peptides displayed on major histocompatibility complexes (MHC). T cells typically recognize peptides presented on self-MHC, which provides important protection against infection and cancer. A portion of the T cell repertoire also has the ability to recognize peptides displayed on non-self MHC, or allogeneic MHC (ALLO-MHC). This phenomenon, known as alloreactivity, is encountered during organ transplantation between genetically distinct individuals. Alloreactivity poses substantial challenges for successful organ transplantation. After allogeneic hematopoietic stem cell transplantation (ALLO-HSCT), transplanted alloreactive donor T cells can attack healthy host tissues, resulting in fatal graft-versus-host-disease. However, alloreactivity after ALLO-HSCT can also be beneficial - in an effect known as graft-versus-leukemia (GVL), alloreactive donor T cells eliminate residual cancer cells, greatly reducing the risk of disease relapse. Efforts have been made to strengthen the GVL response, but GVL and gvhd often CO-occur, resulting in accompanying toxicity against healthy tissues. Despite the well-established phenomenon of gvhd and GVL, our understanding of the interactions that drive these two responses, and how linked they are, remains limited. The overall objective of this proposal is to determine the molecular mechanisms underlying T cell allorecognition in gvhd and GVL through a repertoire-scale examination. I will utilize a single MHC-mismatched bone marrow transplant and tumor model to study alloreactive tcrs against a single MHC in gvhd and GVL, which will allow for comprehensive deconstruction of the underlying mechanisms. Aim 1 will focus on characterizing alloreactive gvhd and GVL T cell repertoires. Experiments will determine the TCR clones involved in gvhd and GVL, their tissue-specificities, and the extent to which they overlap. Aim 2 will then focus on identifying the antigen targets and characterizing the cross- reactivity patterns of these tcrs. We will utilize a library-on-library lentivirus-based screening method developed by our laboratory to map tcrs to their cognate antigens on a repertoire scale, which will reveal the antigens recognized during gvhd and GVL, whether there are shared antigens targeted by these two responses, and the extent of cross-reactivity of individual tcrs. Collectively, these findings will advance our understanding of the molecular interactions driving gvhd and GVL and the extent to which they overlap, providing critical insight for therapeutic efforts to selectively improve GVL responses while limiting gvhd. The proposed research and training plan will equip the candidate with advanced technical skills and knowledge in immunology and engineering, as well as training in rigorous experimental design and interpretation, which together will help the candidate develop into an independent scientist prepared to conduct and lead impactful immune engineering research.