Cellular Mechanisms of Fatal Early-Onset Autoimmunity in Mice with the T Cell-Specific Targeting of TGF Receptor

Transforming growth factor- (TGF-) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF- in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF- signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4+ and CD8+ T cells with TGF--receptor II (TGF-RII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-RII 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-. Thus, TGF- 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.

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Marie JC, Liggitt D, Rudensky AY