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

Mice with a mutation of the z -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 z -associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg /+, skg / skg , to skg / 2 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 / 2 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