Friday, May 3, 2024
5/3/2024
Project Summary T cell-mediated rejection remains a significant barrier to improving long-term allograft survival, underscoring the need for a better understanding of allogeneic T cell responses. Our recent discovery that alloreactive T cells differentiate first into TCF1+Ly108+ effector precursor T (TEP) cells, which then give rise to TCF1¿CXCR6+ terminal effectors, offers a new perspective on eliminating undesired allogeneic T cell responses by understanding and targeting alloreactive TEP cells. To accomplish this, we aim to induce TEP cell dysfunction by targeting essential transcriptional, epigenetic, and metabolic regulators in T cells. Our studies revealed that deleting the transcription factor IRF4, the epigenetic enzyme EZH2, or the glycolytic enzyme LDHA in T cells eliminates the effector differentiation potential of TCF1+Ly108+ TEP cells, preventing them from becoming TCF1¿CXCR6+ terminal effectors. This leads to TEP cell dysfunction and heart transplant acceptance without the need for immunosuppressive treatments. Furthermore, we found that transient treatment with an EZH2 inhibitor alone achieves heart transplant acceptance. Based on these findings, we hypothesize that inducing TEP cell dysfunction is critical for achieving transplant acceptance. To test our hypothesis, we have outlined two specific aims. Aim 1 is to investigate whether the ablation of Irf4, Ezh2, or Ldha induces transplant acceptance by driving “irreversible” TEP cell dysfunction. Aim 2 is to test the hypothesis that inducing TEP cell dysfunction promotes transplant acceptance in wild- type recipients. These studies will offer insights into the induction of TEP cell dysfunction, which has crucial clinical implications for transplantation.
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