Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein(high), Foxp3-expressing CD25+ and CD25- regulatory T cells.
Anomalies of naturally occurring CD4+ regulatory T cells (Treg) cause severe autoimmune/inflammatory diseases in humans and rodents. The transcription factor Foxp3 is currently the most specific marker for natural CD4+ Treg, but it would be useful if other Treg markers, particularly cell surface molecules, could be elucidated. We demonstrate in this study that the vast majority of Foxp3-expressing CD4+ T cells (whether CD25+ or CD25-) show constitutive high-level expression of glucocorticoid-induced TNFR family-related gene/protein (GITR). Transfer of T cell or thymocyte suspensions depleted of GITR(high) cells produces in BALB/c nude mice a wider spectrum and more severe forms of autoimmune diseases than does transfer of similar cell suspensions depleted of CD25+ CD4+ T cells only. Notably, mice that receive cells depleted of GITR(high) populations develop severe multiorgan inflammation that includes fatal autoimmune myocarditis resembling giant cell myocarditis in humans, accompanying high-titer anti-myosin autoantibodies. Similar transfer of GITR(high)-depleted cells from prediabetic NOD mice to NOD-SCID mice accelerates the development of diabetes and induces skeletal muscle myositis and other autoimmune/inflammatory diseases. We conclude that GITR(high), Foxp3-expressing natural Treg, containing both CD25+ and CD25- cell populations, contribute to preventing a variety of autoimmune/inflammatory diseases, and depletion of these cells allows the activation of even weak or rare autoreactive T cells yielding widespread severe autoimmune disease. Diseases induced in this way include many which have been suspected of an autoimmune etiology in humans without much evidence. GITR(high), Foxp3-expressing natural Treg represent a potential target for the treatment and prevention of these diseases.
Ono
Masahiro
M
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Shimizu
Jun
J
Miyachi
Yoshiki
Y
Sakaguchi
Shimon
S
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse