T-cell receptor (TCR) signaling abnormalities and gut dysbiosis are thought to be involved with systemic autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, it is not known whether these mechanisms are interrelated. We have explored the impact of defective TCR signaling on microbiota-driven immune responses and the consequent triggering of systemic autoimmunity. SKG mice, which harbor a point mutation in the zeta-chain-associated protein kinase 70, develop RA on the BALB/c background and SLE on C57BL/6 (B6) background. Interestingly, development of RA and SLE in these mice were significantly attenuated in microbially clean condition. Gut microbiota in these mice were altered due to the alteration of thymic selection by defective TCR signaling, which attenuated the positive selection of microbiota-reactive T cells while facilitating the positive selection of otherwise negatively deleted selected self-reactive T cells. Thus, defective TCR signaling leads to impaired immunity against gut microbiota and self-reactivity, both of which promote the development of systemic autoimmune diseases. In this seminar, gene-microbiota interactions for the development of systemic autoimmunity will be discussed.