Abstract IL -10 is widely accepted as a survival, proliferation, and differentiation factor for B cells. However, IL-10 deficiency accelerates disease progression as the result of autoantibody production in many autoimmune disease models. It was demonstrated that T follicular helper cells (TFH cells) play a key role in helping B cells that are secreting Abs. In this study, we demonstrated a regulatory role for IL-10R signaling on the development and B cell help function of TFH cells in vitro and in vivo. IL-1R subunit β-deficient (Il10rb−/−) Th cells were able to differentiate more readily into TFH cells, as well as secrete more IL-21 and IL-17 compared with wild-type Th cell-derived TFH cells. Increased IL-21 and IL-17 contributed to the enhanced B cell help functions of TFH cells. Further experiments demonstrated that IL-6 and IL-23 from dendritic cells in Il10rb−/− mice contributed to the differentiation of naive Th cells into TFH cells, as well as the generation of IL-21– and IL-17–producing TFH cells. Our results provide useful information for clarifying the immunoregulatory mechanisms associated with IL-10 deficiency in certain autoimmune disease models. This information could also be of benefit for the development of vaccines.