ADAM9 supports regulatory T cell stability through TGF-β-SMAD signaling and is reduced in systemic lupus erythematosus.

BACKGROUND

A Disintegrin and Metalloproteinase 9 (ADAM9) has been implicated in Th17 cell differentiation by activating TGF-β. Given the essential role of TGF-β in maintaining regulatory T (Treg) cell lineage, we hypothesized that ADAM9 supports Treg cell function.

METHODS

We assessed the expression of ADAM9 on the surface membrane of human T cell subsets from patients with systemic lupus erythematosus (SLE) and matched healthy controls by flow cytometry. The effect of ADAM9 deletion on Treg cell function was evaluated using in vitro suppression assays, phospho-SMAD2/3 detection, and an in vivo adoptive-transfer colitis model.

RESULTS

Treg cells exhibited the highest frequency of surface ADAM9+ cells among peripheral T cell subsets. Treg cells, but not other T cell subsets, from SLE patients displayed significantly reduced numbers of ADAM9+ cells compared with healthy controls. Although ADAM9-deficient murine Treg cells suppressed effector T cell proliferation in vitro at levels comparable to those of ADAM9-suficient cells, they demonstrated decreased SMAD2/3 phosphorylation and failed to effectively suppress the ability of CD45RBhi T cells to cause colitis when co-injected in immunodeficient Rag1-/- mice.

CONCLUSION

ADAM9 promotes Treg cell stability and suppressive function in vivo by sustaining TGF-β-SMAD signaling. Reduced ADAM9 expression in SLE Treg cells signifies a potential mechanism contributing to Treg cell dysfunction.