Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function

Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
The Journal of Immunology (Impact Factor: 4.92). 08/2010; 185(4):2295-305. DOI: 10.4049/jimmunol.1000848
Source: PubMed


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.

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Available from: Yoshinaga Ito
    • "In marked contrast, our patients had a distinct phenotype with early onset, severe to life-threatening autoimmune disease and only minor lymphocyte abnormalities and no evidence of immune deficiency (Table 1). In mice, defects in both central and peripheral tolerance have been associated with hypomorphic Zap-70 defects and autoimmune features (Siggs et al., 2007;Au-Yeung et al., 2010;Tanaka et al., 2010). In humans, ZAP70 deficiency can alter the thymic stromal compartment, reduce thymic T reg cell numbers, and develop an autoimmune-prone gene expression profile in CD4 T cells (Roifman et al., 2010;Poliani et al., 2013). "
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    ABSTRACT: A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity. The early onset, severity, and distinctive findings suggested a single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70). Healthy relatives were heterozygous mutation carriers. Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls. Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. Although human ZAP-70 deficiency can have dysregulated T cells, and autoreactive mouse thymocytes with weak Zap-70 signaling can escape tolerance, our patients' combination of hypomorphic and activating mutations suggested a new disease mechanism and produced previously undescribed human ZAP-70-associated autoimmune disease.
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    • "However all Skg/Skg mice developed severe arthritis after intraperitoneal injection of 20 mg mannan (purchased from Sigma) dissolved in 200 µl PBS. Skg/WT heterozygous mice display altered thymic selection [36], [37] and alterations of the Vβ thymic repertoire [37] qualitatively similar to the ones found in Skg/Skg mice, however they do not develop spontaneous [35] or polysaccharide-induced (our unpublished observation) arthritis. Clinical scoring of arthritis was carried out as described [35]. "
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    • "Germ-free SKG homozygous mice do not develop disease, but stimulation of pattern-recognition receptors induces onset of disease which is T cell-dependent (Yoshitomi et al., 2005). In contrast, SKG heterozygous mice develop spontaneous autoimmune disease emphasizing the impact of graded TCR stimulation (Tanaka et al., 2010). Autoimmune manifestations are also seen in ZAP70 hypomorphic mutants that allow the study of the impact of graded T cell receptor signaling strengths (Siggs et al., 2007). "
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