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B7-H4 Modulates Regulatory CD4+ T Cell Induction and Function via Ligation of a Semaphorin 3a/Plexin A4/Neuropilin-1 Complex.


ABSTRACT: 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.

SUBMITTER: Podojil JR 

PROVIDER: S-EPMC6894186 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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B7-H4 Modulates Regulatory CD4<sup>+</sup> T Cell Induction and Function via Ligation of a Semaphorin 3a/Plexin A4/Neuropilin-1 Complex.

Podojil Joseph R JR   Chiang Ming-Yi MY   Ifergan Igal I   Copeland Ronald R   Liu Linda N LN   Maloveste Sebastien S   Langermann Solomon S   Liebenson David D   Balabanov Roumen R   Chi Hongbo H   Chen Lieping L   Vignali Dario A A DAA   Miller Stephen D SD  

Journal of immunology (Baltimore, Md. : 1950) 20180613 3


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<sup>+</sup> T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3<sup>+</sup> T cells within the tumor microenvironment. Recent data indica  ...[more]

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