Interleukin 17 (IL-17)-producing helper T cells (T_H17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T_H17 cells are main drivers of autoimmune tissue injury. However, not all T_H17 cells are pathogenic; in fact, T_H17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing T_H17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic T_H17 cells. Moreover, TGF-β3-induced T_H17 cells were functionally and molecularly distinct from TGF-β1-induced T_H17 cells and had a molecular signature that defined pathogenic effector T_H17 cells in autoimmune disease.