Conversion of alloantigen-specific CD8+ T cell anergy to CD8+ T cell priming through in vivo ligation of glucocorticoid-induced TNF receptor.
In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-gamma and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.
Kim
Juyang
J
Immunomodulation Research Center (IRC) and Department of Biological Science, University of Ulsan, San29, Mukeo-dong, Nam-ku, Ulsan, Republic of Korea.
Choi
Woon S
WS
Kang
Hyun
H
Kim
Hye J
HJ
Suh
Jae-Hee
JH
Sakaguchi
Shimon
S
Kwon
Byungsuk
B
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D017635:Clonal Anergy / Q000276:immunology*; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006086:Graft vs Host Disease / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D017475:Receptors, Nerve Growth Factor / Q000276:immunology* / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007519:Isoantigens; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse