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PMID:16973387

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Citation

Marie, JC, Liggitt, D and Rudensky, AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25:441-54

Abstract

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.

Links

PubMed Online version:10.1016/j.immuni.2006.07.012

Keywords

Animals; Antigens, Surface/metabolism; Autoimmune Diseases/genetics; Autoimmune Diseases/metabolism; Autoimmune Diseases/mortality; Cells, Cultured; Immune Tolerance/genetics; Lectins, C-Type/metabolism; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; NK Cell Lectin-Like Receptor Subfamily B; Receptors, Transforming Growth Factor beta/deficiency; Receptors, Transforming Growth Factor beta/genetics; Receptors, Transforming Growth Factor beta/physiology; T-Lymphocytes/immunology; T-Lymphocytes/metabolism; Time Factors

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