B7-H4 modulates regulatory CD4⁺T cell induction and function via ligation of a semaphorin 3a/Plexin A4/Neuropilin-1 Complex

The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4⁺ T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3⁺ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig-induced inhibition of inflammatory CD4⁺ T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3⁺ T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4⁺ T cell number and function.