DETCs do not express many of the usual coreceptors that are important for αβ T-cell activation, such as CD4 or CD8, or the costimulatory molecule CD28. It is thought that, similar to αβ T cells, complete activation of DETCs requires costimulatory signals. Bonneville 9 pointed out that plexin B2 is broadly expressed on many epithelial tissues where resident CD100-expressing γδ T cells are located, suggesting that the Sema 4D/CD100–plexin B2 interaction may play a more general role in the immune control of the integrity of epithelial barriers. It is not surprising to identify Sema 4D/CD100-plexin B as a counter-receptor, because many counter-receptors have already been well documented in the B7-CD28 family and TNF–TNFR superfamilies.Īnother important point in Witherden's paper 8 is that the Sema 4D/CD100 molecule on γδ T cells mediates a function involved in innate immunity. This is the first example indicating that Sema 4D/CD100 is not only a ligand for plexin B1 or CD72 but also a direct signaling receptor in mediating Sema 4D/CD100-plexin B's biological functions. The morphological changes in DETCs that precede cutaneous wound healing appear to be associated with the activation of key actin regulators in response to Sema 4D/CD100's binding with its ligand. 8 demonstrated that the interaction of Sema 4D/CD100 with plexin B2 plays a key role in activating skin-resident γδ T cells (DETCs) in mice to respond to tissue damage ( Figure 1c). These morphologically rounded DETCs release keratinocyte growth factor type 1 (KGF1) and KGF2, which may induce the proliferation and migration of keratinocytes and the restoration of epithelial integrity. ( c) Damaged keratinocytes produce a self-antigen, plexin B2, and cocksackie adenovirus receptor (CAR), which can be recognized by the γδ T-cell receptor (TCR), Sema 4D/CD100, and the junctional adhesion molecule-like molecule (JAML), respectively, of dendritic epidermal γδ T cells (DETCs). ( b) The binding of Sema 4D/CD100 molecules, which can be in both membrane-bound form (expressed on T cells or tumor cells) and soluble form (sCD100) (shed from activated T cells or tumor cells), to the high-affinity receptor plexin B1, which is expressed on endothelial and epithelial cells, induces angiogenesis and endothelial cell migration. ( a) As a ligand, the ligation of Sema 4D/CD100 with the low-affinity receptor CD72 stimulates the activation of, proliferation of and antibody production by B cells, promotes the maturation of and antigen presentation by dendritic cells (DCs), and induces the production of cytokines (IL-12, TNF-α, IL-6 and IL-8) by monocytes (Mo). Multiple functions mediated by Sema 4D/CD100-plexin B counter-receptors. The high-affinity Sema 4D/CD100 receptor plexin B1 is mainly expressed on endothelial cells and epithelial cells ( Figure 1b), 6 whereas plexin B2 and plexin C1 are low-affinity receptors for Sema 4D/CD100. 5 At least three Sema 4D/CD100 receptors are plexin family members. ![]() CD72, a member of the C-type lectin family, is a low-affinity Sema 4D/CD100 receptor that is expressed on immune cells, such as B cells, dendritic cells, macrophages and mast cells ( Figure 1a). ![]() The Sema 4D/CD100 molecule can bind to several receptors. 3 Unlike the prototypical semaphorins, which are neuronal chemorepellents, Sema 4D/CD100 together with Sema 3A, Sema 4A, Sema 6D and Sema 7A have been described as ‘immune semaphorins', because they are expressed on T cells, B cells, natural killer cells and dendritic cells, and exhibit a variety of immunological functions. In 1996, 3 years after the discovery of the semaphorin family, 2 the CD100 gene was cloned and identified as the first semaphorin with immune system functions. 1 Hence, this molecule has been designated CD100 by the International Workshop on Human Leukocyte Differentiation Antigen. It was expressed on T lymphocytes that had been activated with CD3 monoclonal antibody or phytohaemagglutinin. The discovery of Sema 4D can be dated to 1992, when Boumsell's team reported a novel 150-kDa glycoprotein dimer.
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