| First Author | Tanaka S | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 4 | Pages | 2295-305 |
| PubMed ID | 20644168 | Mgi Jnum | J:162619 |
| Mgi Id | MGI:4819424 | Doi | 10.4049/jimmunol.1000848 |
| Citation | Tanaka S, et al. (2010) Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J Immunol 185(4):2295-305 |
| abstractText | 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. |
