Peroxisome proliferator-activated receptor γ deficiency in T cells accelerates chronic rejection by influencing the differentiation of CD4+ T cells and alternatively activated macrophages

• Published in: PloS one Vol. 9; no. 11; p. e112953
• Main Authors: Huang, Xiaofan, Ren, Lingyun, Ye, Ping, Cheng, Chao, Wu, Jie, Wang, Sihua, Sun, Yuan, Liu, Zheng, Xie, Aini, Xia, Jiahong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.11.2014; Public Library of Science (PLoS)
• Subjects: Animals; Atherosclerosis; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - physiology; Cell activation; Cell culture; Cell Differentiation; Cell survival; Cells, Cultured; Coculture Techniques; Coronary vessels; Cytokines; Cytometry; Diabetes; Differentiation (biology); Disease Models, Animal; Flow cytometry; Gene expression; Gene Knockout Techniques; Graft rejection; Graft Rejection - immunology; Graft Rejection - pathology; Heart diseases; Heart surgery; Heart Transplantation; Helper cells; Histocompatibility antigen H-2; Histology; Hospitals; Immune system; Immunohistochemistry; Immunological tolerance; Induced polarization; Lymphocytes; Lymphocytes T; Macrophage Activation; Macrophages; Major histocompatibility complex; Medical research; Medicine and Health Sciences; Metabolism; Mice; Monocytes; Monocytes - cytology; Pioglitazone; Polarization; Polymerase chain reaction; PPAR gamma - genetics; PPAR gamma - metabolism; Pulmonary arteries; Rejection; Rodents; Science; Side effects; Subpopulations; Survival; Thoracic surgery; Transcription; Transcription factors; Transplantation; Transplants & implants; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0112953

In a previous study, activation of the peroxisome proliferator-activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ-induced protective effect was unclear. A chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regulatory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM). T cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival. PPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects.