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.

Grant Number: 1R56AI192360-01
NIH Institute/Center: NIH
Principal Investigator: Wenhao Chen