Article

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: 5.52). 08/2010; 185(4):2295-305. DOI:10.4049/jimmunol.1000848
Source: PubMed

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.

0 0
 · 
0 Bookmarks
 · 
173 Views
  • [show abstract] [hide abstract]
    ABSTRACT: Loss of ζ-associated protein 70 (Zap70) results in severe immunodeficiency in humans and mice due to the critical role of Zap70 in TCR signalling. Here we describe a novel mouse strain generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, with the reduced protein stability (rps) mutation in Zap70. The A243V rps mutation resulted in decreased Zap70 protein and a reduced duration of TCR-induced calcium responses, equivalent to that induced by a 50% decrease in catalytically-active Zap70. The reduction of signalling through Zap70 was insufficient to substantially perturb thymic differentiation of conventional CD4 and CD8 T cells, although Foxp3(+) regulatory T cells demonstrated altered thymic production and peripheral homeostasis. Despite the mild phenotype, the Zap70(A243V) variant lies just above the functional threshold for TCR signalling competence, as T cells relying on only a single copy of the Zap70(rps) allele for TCR signalling demonstrated no intracellular calcium response to TCR stimulation. This addition to the Zap70 allelic series indicates that a rate-limiting threshold for Zap70 protein levels exists at which signalling capacity switches from nearly intact to effectively null. This article is protected by copyright. All rights reserved.
    Immunology 10/2013; · 3.71 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Immune aging is best known for its immune defects that increase susceptibility to infections and reduce adaptive immune responses to vaccination. In parallel, the aged immune system is prone to autoimmune responses and many autoimmune diseases increase in incidence with age or are even preferentially encountered in the elderly. Why an immune system that suboptimally responds to exogenous antigen fails to maintain tolerance to self-antigens appears to be perplexing. In this review, we will discuss age-associated deviations in the immune repertoire and the regulation of signaling pathways that may shed light on this conundrum.
    Frontiers in Immunology 01/2013; 4:131.
  • [show abstract] [hide abstract]
    ABSTRACT: Induction of specific immune tolerance to grafts remains the sought-after standard following transplantation. Defined by expression of the Foxp3 (forkhead box protein 3) transcription factor, the regulatory T-cell (Treg) lineage has been noted to exert potent immunoregulatory functions that contribute to specific graft tolerance. In this review, we discuss the known signals and pathways which govern Treg development, both in the thymus and in peripheral sites, as well as lineage maintenance and homeostasis. In particular, we highlight the roles of T-cell receptor signaling, CD28 costimulation, and signals through phosphatidyl inositol 3-kinase (PI3K) and related metabolic pathways in multiple aspects of Treg biology.
    Immunological Reviews 03/2014; 258(1):117-31. · 12.16 Impact Factor

Full-text (2 Sources)

View
22 Downloads
Available from
Feb 21, 2013