Self-antigen recognition by TGFβ1-deficient T cells causes their activation and systemic inflammation

Abstract

To investigate whether the multifocal inflammatory disease in TGFβ1-deficient mice is caused by self-antigen (self-Ag)-specific autoreactive T cells, or whether it is caused by antigen independent, spontaneous hyperactivation of T cells, we have generated Tgfb1 −/− and Tgfb1 −/− Rag1 −/− mice expressing the chicken OVA-specific TCR transgene (DO11.10). On a Rag1-sufficient background, Tgfb1 −/− DO11.10 mice develop a milder inflammation than do Tgfb1 −/− mice, and their T cells display a less activated phenotype. The lower level of activation correlates with the expression of hybrid TCR (transgenic TCRβ and endogenous TCRα), which could recognize self-Ag and undergo activation. In the complete absence of self-Ag recognition (Tgfb1 −/− DO11.10 Rag1 −/− mice) inflammation and T-cell activation are eliminated, demonstrating that self-Ag recognition is required for the hyper-responsiveness of TGFβ1-deficient T cells. Thus, TGFβ1 is required for the prevention of autoimmune disease through its ability to control the activation of autoreactive T cells to self-Ag.

TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

“…This underscores the vital, nonredundant role played by TGF-␤1 in regulating the response of CD4 ϩ T cells to self-Ags presented in the periphery. In support of this, restricting the TCR repertoire available to CD4 ϩ T cells through expression of a transgenic TCR prevents the development of inflammation and end-organ damage in TGF-␤1 Ϫ/Ϫ mice (9,10). Along with the current work, these data strongly suggest that the inflammatory pathology in TGF-␤1 Ϫ/Ϫ mice results from the interaction of autoreactive CD4 ϩ T cells with self-Ags.…”

“…The majority of CD4 ϩ T cells in the liver and spleen from TGF-␤1 Ϫ/Ϫ mice express low levels of CD62 ligand (CD62L) 3 and high levels of CD44 and VLA-4, a surface expression profile consistent with TCR activation (4), although LPS alone can also induce similar T cell surface expression profiles (8). Evidence in support of the specific Ag model has been published recently; experimentally restricting the TCR repertoire available to CD4 ϩ T cells in TGF-␤1 Ϫ/Ϫ mice, through breeding of the TGF-␤1 Ϫ/Ϫ mouse with the OVA-specific DO11.10 TCR-transgenic mouse, prevented the development of T cell activation and tissue pathology (9,10). Further implicating a pathologic role for self-Ags, TGF-␤1 Ϫ/Ϫ mice raised in germfree conditions nevertheless develop end-organ inflammatory pathology, indicating that the presence of intestinal microflora is not necessary for disease (11).…”

TGFβ1 and Treg cells: alliance for tolerance

“…These data suggest that TGFβ1-deficient T cells do not require co-stimulatory signals through CD28 for their activation and autoimmune response [2]. Recently, we demonstrated, in Tgfb1 −/− mice, that elimination of self-antigen-reactive TCR-bearing T cells by genetic combination strongly inhibits activation of T cells and eliminates inflammation [33].We and others have also shown, using TCR-transgenic mice, that T reg -cell generation and maintenance in the periphery is not TGFβ1 dependent [39] (R. Bommireddy et al, unpublished). This suggests that TGFβ1 is important for the prevention of self-reactive T-cell activation, T reg -cell suppressor function or both.…”

“…They have also found that TGFβ1-deficient T reg cells fail to inhibit IFN production and T-cell activation in vivo and in vitro and also fail to protect mice from developing colitis in the adoptive-transfer model of colitis [42]. TGFβ1-independent T reg cells are unlikely to induce dominant tolerance because Tgfb1 −/− mice die at approximately weaning age from multi-organ autoimmunity [2,33].…”

“…Tgfb1 −/− mice die at weaning age from a multifocal autoimmune disease caused by self-reactive T cells [2,33]. Phenotypes of Tgfb1 −/− mice on various gene-KO backgrounds are summarized in Table 2.…”