Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor.
Transforming growth factor-beta (TGF-beta) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-beta in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-beta signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4+ and CD8+ T cells with TGF-beta-receptor II (TGF-betaRII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-betaRII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-gamma. Thus, TGF-beta signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity.
Marie
Julien C
JC
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington 98195, USA. marie@cervi-lyon.inserm.fr
Liggitt
Denny
D
Rudensky
Alexander Y
AY
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D002478:Cells, Cultured; D007108:Immune Tolerance / Q000235:genetics; D037181:Lectins, C-Type / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors
D000954:Antigens, Surface; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018125:Receptors, Transforming Growth Factor beta