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

J Immunol. 2018 Aug 1;201(3):897-907. doi: 10.4049/jimmunol.1700811. Epub 2018 Jun 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cells, Cultured
  • Female
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neuropilin-1 / metabolism*
  • PTEN Phosphohydrolase / metabolism
  • Receptors, Cell Surface / metabolism*
  • Semaphorin-3A / metabolism*
  • Tumor Microenvironment / immunology
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / metabolism*


  • Forkhead Transcription Factors
  • Plxna4 protein, human
  • Receptors, Cell Surface
  • SEMA3A protein, human
  • Semaphorin-3A
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • VTCN1 protein, human
  • Neuropilin-1
  • PTEN Phosphohydrolase