Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function
ABSTRACT Mice with a mutation of the zeta-associated protein of 70 kDa gene (skg mutation) are genetically prone to develop autoimmune arthritis, depending on the environment. In a set of mice with the mutation, the amount of zeta-associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg/+, skg/skg, to skg/- mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3(+) natural regulatory T cells (Tregs) and their respective functions. Consequently, skg/- mice spontaneously developed autoimmune arthritis even in a microbially clean environment, whereas skg/skg mice required stimulation through innate immunity for disease manifestation. After Treg depletion, organ-specific autoimmune diseases, especially autoimmune gastritis, predominantly developed in +/+, at a lesser incidence in skg/+, but not in skg/skg BALB/c mice, which suffered from other autoimmune diseases, especially autoimmune arthritis. In correlation with this change, gastritis-mediating TCR transgenic T cells were positively selected in +/+, less in skg/+, but not in skg/skg BALB/c mice. Similarly, on the genetic background of diabetes-prone NOD mice, diabetes spontaneously developed in +/+, at a lesser incidence in skg/+, but not in skg/skg mice, which instead succumbed to arthritis. Thus, the graded attenuation of TCR signaling alters the repertoire and the function of autoimmune T cells and natural Tregs in a progressive manner. It also changes the dependency of disease development on environmental stimuli. These findings collectively provide a model of how genetic anomaly of T cell signaling contributes to the development of autoimmune disease.
Full-textDOI: · Available from: Yoshinaga Ito, Aug 21, 2015
- SourceAvailable from: Hyungwook Lim
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- "Recent findings that attenuation of the function of proximal elements in the TCR signalling pathway, such as Zap-70, can lead to autoimmunity (Tanaka et al, 2010) are particularly encouraging in this regard, and will greatly inform our future efforts to better understand the possible role of HDAC7 in the genetics of human autoimmune disease. "
ABSTRACT: Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-ΔP) in thymocytes. We find that HDAC7-ΔP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance.The EMBO Journal 10/2012; 31(23). DOI:10.1038/emboj.2012.295 · 10.75 Impact Factor
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- "Negative selection and T reg cell development are both promoted by, and dependent on, highaffinity TCR–ligand interactions, as well as TCR signals, and they are thought to share common signaling requirements (Jordan et al., 2001; Starr et al., 2003; Apostolou et al., 2002; Carter et al., 2005; Ordoñez-Rueda et al., 2009). Consistent with this idea, mutations of key signaling intermediates downstream of the TCR, including ZAP-70 and LAT, result in defects in both negative selection and T reg cell development (Sakaguchi et al., 2003; Sommers et al., 2005; Siggs et al., 2007; Hsu et al., 2009; Chuck et al., 2010; Tanaka et al., 2010). It was recently reported that attenuation of TCR-proximal signaling by inactivation of the TCR chain immunoreceptor tyrosine based activation motifs (ITAMs) in mice results in a selective defect in negative selection that leads to a rapidly progressive, fatal, multi-system autoimmune disease (Holst et al., 2008). "
ABSTRACT: Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR ζ chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous ζ regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.Journal of Experimental Medicine 09/2012; 209(10):1781-95. DOI:10.1084/jem.20120058 · 13.91 Impact Factor
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- ". A possible mechanism of SKG arthritis. SKG thymus produce self-reactive T cells due to skg ZAP70 mutation (1)  . These T cells strongly recognize selfantigen/MHC complexes displayed by APCs and become activated to express CD40L (2), further leading to up-regulation of the expression of B7 (CD80/CD86) by APC via CD40/CD40L interaction (3) and stimulating APC secretion of IL-6 (4) . "
ABSTRACT: A hypomorphic mutation of the gene encoding zeta-associated protein-70 (ZAP-70), a signaling molecule in T cells, produces autoimmune arthritis in mice under a microbially conventional condition but not in a clean environment. The genetic anomaly alters thymic selection of self-reactive T cells as well as natural regulatory T cells and their respective functions. Highly self-reactive polyclonal T cells, including arthritogenic ones, thus produced by the thymus strongly recognize self-antigens presented by antigen-presenting cells, stimulate them to up-regulate co-stimulatory molecules and secrete cytokines that drive naïve self-reactive T cells to differentiate into autoimmune effector Th17 cells. Administration of microbial products and activation of complement can facilitate the differentiation, evoking clinically overt arthritis in a microbially clean environment. Furthermore, mutation-dependent graded attenuation of T cell receptor signaling alters disease phenotypes and the dependency of disease occurrence on the environment. These findings provide a model of how genetic and environmental factors, in association, cause autoimmune diseases such as rheumatoid arthritis.FEBS letters 12/2011; 585(23):3633-9. DOI:10.1016/j.febslet.2011.10.026 · 3.34 Impact Factor