Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor

Immunity. 2006 Sep;25(3):441-54. doi: 10.1016/j.immuni.2006.07.012.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Antigens, Surface
  • Lectins, C-Type
  • NK Cell Lectin-Like Receptor Subfamily B
  • Receptors, Transforming Growth Factor beta