Genetics and gut microbiota contribute to the development of autoimmune diseases. SKG mice, which harbor a point mutation in the ZAP70 gene, develop autoimmune arthritis in BALB/c background and systemic lupus erythematosus in C57BL/6 background. Defective TCR signaling by ZAP70 mutation alters thymic selection thresholds and allows the positive selection of otherwise negatively selected self-reactive T cells. On the other hand, defective TCR signaling attenuates the positive selection of certain microbiota-reactive T cells, which lead to impaired IgA synthesis at mucosal site and gut dysbiosis. Gut dysbiosis, in turn, promotes autoimmunity via driving Th17 differentiation. Thus, defective TCR signaling leads to autoimmunity by altering thymic selection thresholds of self-reactive T cells and microbiota-reactive T cells. In this review, genomics-microbiota interactions for the development of autoimmunity will be discussed with the special focus on the recent finding obtained from animal models of autoimmunity with defective TCR signaling.