TGF-β Inhibition of CTL Re-Stimulation Requires Accessory Cells and Induces Peroxisome-Proliferator-Activated Receptor-Gamma (PPAR-γ)

Effective cellular immunity to Epstein-Barr virus (EBV), necessary to prevent or cure many post-transplant lymphoproliferative disorders (PTLD), can be inhibited by transforming growth factor-beta (TGF-β). In vitro, TGF-β inhibits memory CTL re-stimulation from whole PBMC. We show that the effect of TGF-β on CTL re-stimulation is not directly on the T cell, but requires an accessory cell (AC) population. Further, pre-treatment of AC with TGF-β significantly reduces memory CTL re-stimulation and suppresses delayed type hypersensitivity (DTH) responses. Addition of exogenous interferon-gamma to the AC overcomes the effects of TGF-β. TGF-β pre-treatment also up-regulates expression of peroxisome-proliferator-activated receptor-gamma (PPAR-γ) in CD14+ AC. Importantly, pre-treatment of AC with the PPAR-γ ligand, ciglitazone, results in significantly reduced memory CTL re-stimulation. Thus, the effects of TGF-β in this system may be mediated in part via PPAR-γ, and PPAR-γ activation could have significant inhibitory effects on memory T-cell responses by affecting AC function. These data have important implications in understanding how memory CTL are re-stimulated and function to prevent disease, especially PTLD.