Prior consensus held that medication-related osteonecrosis of the jaw (MRONJ) lesion was composed of necrotic bone; however, more recent studies have identified inflammatory infiltrates in the lesion. Herein, we report that remarkably elevated infiltrating gamma delta T cells (90% of lymphocytes) express Semaphorin 4D (Sema4D) in human patient with MRONJ lesion, whereas gamma delta T cells only account for 2-5% of lymphocytes in blood. Importantly, Sema4D is implicated in the pathogenesis of T cell-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Indeed, in a mouse model of MRONJ, an elevated number of gamma delta T, but not alpha beta T, cells infiltrating in the MRONJ-like lesion was observed. Both elevated soluble Sema4D (sSema4D) production accompanied by pro-inflammatory cytokines, including TNF-alpha IFN-gamma and IL-1 beta, and Sema4D-expressing gamma delta T cells were detected in mouse MRONJ-like lesion. Activated gamma delta T cells produced sSema4D in vitro, which could promote TNF-alpha production from macrophages. Meanwhile, gamma delta T cell-KO mice were resistant to the induction of MRONJ and, hence, showed no elevation of local productions of Sema4D and TNF-alpha. Finally, systemic administration of anti-Sema4D neutralizing mAb suppressed the onset of MRONJ in wild-type mice in conjunction with diminished level of TNF-alpha. These results suggested a critical pathogenic engagement of Sema4D produced by gamma delta T cells in the development of MRONJ. (C) 2016 Published by Elsevier Inc.