Possible pathogenic engagement of soluble Semaphorin 4D produced by γδT cells in medication-related osteonecrosis of the jaw (MRONJ)

•γδT, but not αβT, cells prone to migrate into MRONJ site in both humans and mice.•Upon activation, γδT cells produce more sSema4D than αβT cells, in vitro.•sSema4D promotes the production of TNF-α from macrophages.•γδT-KO mice neither develop MRONJ nor produce sSema4D or TNF-α in the lesion.•Anti-Sema4D mAb suppressed the onset of MRONJ in wild-type mice.

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 γδT cells (90% of lymphocytes) express Semaphorin 4D (Sema4D) in human patient with MRONJ lesion, whereas γδT 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 γδT, but not αβT, cells infiltrating in the MRONJ-like lesion was observed. Both elevated soluble Sema4D (sSema4D) production accompanied by pro-inflammatory cytokines, including TNF-α IFN-γ and IL-1β, and Sema4D-expressing γδT cells were detected in mouse MRONJ-like lesion. Activated γδT cells produced sSema4D in vitro, which could promote TNF-α production from macrophages. Meanwhile, γδT cell-KO mice were resistant to the induction of MRONJ and, hence, showed no elevation of local productions of Sema4D and TNF-α. Finally, systemic administration of anti-Sema4D neutralizing mAb suppressed the onset of MRONJ in wild-type mice in conjunction with diminished level of TNF-α. These results suggested a critical pathogenic engagement of Sema4D produced by γδT cells in the development of MRONJ.