TGF-beta inhibition of CTL re-stimulation requires accessory cells and induces peroxisome-proliferator-activated receptor-gamma (PPAR-gamma).
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-beta). In vitro, TGF-beta inhibits memory CTL re-stimulation from whole PBMC. We show that the effect of TGF-beta 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-beta 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-beta. TGF-beta pre-treatment also up-regulates expression of peroxisome-proliferator-activated receptor-gamma (PPAR-gamma) in CD14(+) AC. Importantly, pre-treatment of AC with the PPAR-gamma ligand, ciglitazone, results in significantly reduced memory CTL re-stimulation. Thus, the effects of TGF-beta in this system may be mediated in part via PPAR-gamma, and PPAR-gamma 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.
VanBuskirk
A M
AM
Division of Surgical Oncology, Department of Surgery, Ohio State University Comprehensive Cancer Center, Columbus, USA. vanbuskirk.1@osu.edu
Lesinski
G B
GB
Nye
K J
KJ
Carson
W E
WE
Yee
L D
LD
D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; C039671:ciglitazone