LDHA-dependent T-cell effector programs in heart transplantation

Project Summary This proposal addresses the significant challenge of T cell-mediated rejection in heart transplantation by investigating the role of lactate dehydrogenase A (LDHA) in T-cell effector differentiation. Effector T cells play a critical role in rejecting transplanted hearts. Our recent studies have revealed a novel framework in which naive alloreactive T cells activate, expand as effector precursor T (TEP) cells, and then differentiate into effector T cells that attack the heart allograft. This differentiation process requires precise effector gene expression, which we hypothesize is regulated by LDHA through metabolic- epigenetic pathways. LDHA is a key enzyme in aerobic glycolysis, converting pyruvate to lactate, a process more active in effector T cells compared to TEP cells. In mice with T cell-specific LDHA deletion, alloreactive TEP cells still proliferate but fail to differentiate into effector cells, resulting in heart allograft tolerance without the need for immunosuppression. This discovery highlights LDHA as a critical regulator of effector T- cell function. The proposal tests the hypothesis that LDHA regulates effector gene expression through two metabolic-epigenetic pathways: Aim 1 investigates whether LDHA increases cytosolic acetyl-CoA levels, promoting histone acetylation at effector gene loci. Aim 2 explores whether LDHA-mediated lactate production enhances histone lactylation and increases the NAD+/NADH ratio, supporting effector gene expression. Aim 3 evaluates whether inhibiting LDHA with the selective inhibitor FX11 can induce heart transplant tolerance, mimicking the effects of genetic LDHA deletion. This study will provide new insights into how LDHA regulates effector T-cell differentiation and offer innovative therapeutic strategies for improving transplant outcomes.