Systemic lupus erythematosus is an autoimmune disease with comprehensive immune cell disorders. Recent studies suggested that pro-inflammatory cytokine IL-17 plays important role in lupus, leaving the cellular sources and their pathogenic and physiologic characters largely unknown. In the current study, by using lupus-prone MRL/lpr mice, we demonstrated that Th17 response prevails in lupus disease regarding significantly accumulated serum IL-17, increased IL-17-producing splenocytes, and elevated phospho-STAT3 in CD4+ T cells. Intracellular staining revealed that unusual CD4+ B220+ T cells are major IL-17-producing cells, whereas conventional CD4+ B220− T cells are major IFN-γ-producing cells. Subsequent studies showed that CD4+ B220+ cells contains both αβ and γδ T cells in the spleen and thymus of MRL/lpr mice. Further study showed that around 60% of γδ T cells in MRL/lpr mice co-express both B220 and CD4 on their surface, and are the major RORγt+ cells in MRL/lpr mice. Finally, CD4+ B220+ T cells alone do not proliferate, but could enhance the proliferation and IFN-γ-production of conventional CD4+ B220− T cells. Our findings suggest the pathogenic role of unusual CD4+ B220+ T cells in lupus disease in MRL/lpr mice according to their IL-17-producing ability and stimulatory function for conventional CD4+ B220− T cells.