Peroxisome proliferator-activated receptor delta loss reduces alloreactive CD4 T cell proliferation and lessens graft-versus-host-disease severity 2260348

Introduction Our lab previously demonstrated that murine alloreactive T cells increase fatty acid oxidation (FAO) during graft-versus-host disease (GVHD), and more recently, we observed higher levels of peroxisome proliferator-activated receptor delta (PPARγ) in donor T cells after transplantation. Therefore, we hypothesize that PPARγ-driven FAO in T cells plays a role in GVHD development. Methods We first conducted in vitro assays on wild-type (WT) T cells using a PPARγ-specific agonist. Then, we created a T cell conditional PPARγ knockout (KO) mouse strain to supply donor T cells for our GVHD model. Results We found that GW501516-treated T cells stimulated by MLR had increased transcript levels of FAO genes: a 2-fold increase in acetyl-CoA acyltransferase 2 (Acaa2), a 4-fold increase in perilipin-2 (Plin2) in CD8 T cells as well as a 6-fold (Acaa2) and an 8-fold (Plin2) increase in CD4 T cells (multiple t-test, p = 0.01). PPARγ agonism of MLR-stimulated T cells also increased FAO in CD8 and CD4 T cells in radiolabeled palmitate oxidation assays (unpaired t-test, p = 0.01). In our GVHD model, deleting PPARγ in donor T cells improved survival (median: WT = 20; KO = 33) compared to WT donor T cell recipients (one-way ANOVA, p = 0.01). Notably, on Day 7 after transplantation, we saw a significant decrease in proliferating donor CD4 T cells, but not CD8 T cells, from PPARγ KO donors. We also noted reduced proliferation of CD4 PPARγ KO T cells on Day 5 post-transplant and during in vitro stimulation assays (Walsh t-test, p = 0.01). In the context of a CD4-only GVHD model, survival in PPARγ KO recipients was even more improved compared to WT recipients (median: WT = 51; KO=undef). Flow cytometry and histology analysis on Day 21 post-transplant showed lower donor lymphocyte frequencies and fewer total donor CD4+ T cells in the liver and small intestines of PPARγ KO recipients. Conclusion These data overall indicate that the loss of PPARγ impairs the ability of donor T cells to infiltrate target organs during GVHD progression.