Overexpression of program death-1 in T cells has mild impact on allograft survival.
Program death-1 (PD-1), an inhibitory receptor upregulated on T cells upon TCR stimulation, has been shown to attenuate a number of immune responses in vivo, including acute allograft rejection. We tested whether constitutive expression of PD-1 would further inhibit allograft rejection. To this end, we generated transgenic mice expressing T-cell-restricted PD-1 under the control of the Lck proximal promoter and CD2 locus control. PD-1 transgenic (PD-1-Tg) mice did not develop gross abnormalities of thymic development and displayed normal numbers of thymocyte subsets and peripheral T cells. In vitro, PD-1-Tg T cells had reduced proliferative and cytokine secretion capacity upon TCR stimulation and cross-linking of PD-1 resulted in diminished phosphorylation of protein kinase C-theta and Akt, as well as increased activation of the phosphate and tensin homolog. However, only T-cell responses to minor but not major mismatches were reduced in vitro. Similarly, PD-1-Tg mice exhibited prolonged survival of cardiac allografts only in mice transplanted with heart allografts expressing multiple minor mismatches and treated with suboptimal doses of cyclosporine A. We conclude that genetic engineering of T cells to express PD-1 constitutively has only a mild impact on allograft survival.
Chen
Luqiu
L
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Hussien
Yassir
Y
Hwang
Kwang Woo
KW
Wang
Ying
Y
Zhou
Ping
P
Alegre
Maria-Luisa
ML
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D015153:Blotting, Western; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014184:Transplantation, Homologous
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D007166:Immunosuppressive Agents; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016572:Cyclosporine; D004247:DNA