The CD100 Receptor Interacts with Its Plexin B2 Ligand to Regulate Epidermal γδ T Cell Function

Abstract

γδ T cells respond rapidly to keratinocyte damage in the skin, providing essential contributions to the wound healing process, but the molecular interactions regulating their response are unknown. Here we identify a role for the interaction of plexin B2 and the CD100 receptor in epithelial repair. In vitro blocking of plexin B2 or CD100 inhibited γδ T cell activation. Furthermore, CD100 deficiency in vivo resulted in delayed repair of cutaneous wounds due to a disrupted γδ T cell response to keratinocyte damage. Direct ligation of CD100 in γδ T cells induced cellular rounding via signals through ERK kinase and cofilin. Defects in this rounding process were evident in the absence of CD100-mediated signals, thereby providing a mechanistic explanation for the defective wound healing in CD100-deficient animals. The discovery of immune functions for plexin B2 and CD100 provides insight into the complex cell-cell interactions between epithelial resident γδ T cells and the neighboring cells they support.

Genetic dissection of plexin signaling in vivo

“…This crucial importance of the GAP domain of plexins during mouse development is in line with findings in Drosophila and Caenorhabditis elegans, where the GAP domains of PlexA and PLX-1 have been shown to be critical for development of the nervous system (47,48). Owing to the perinatal lethality of Plexin-B2 and Plexin-D1 GAP domain mutant mice, we could not systematically address the functional significance of the GAP domain at postnatal stages of development or in physiological and pathophysiological processes in the adult [e.g., for Plexin-B2 in the postnatal migration and proliferation of neuroblasts (26) and in wound healing (49), or for Plexin-D1 in postnatal development of the nervous system (34,35) and in angiogenesis (36,50)]. Further studies using mice with floxed alleles crossed to the BAC transgenic and specific Cre mice will be required to address these open questions.…”

Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors

“…Activation of PLEXIN-B1, the high-affinity SEMA4D receptor, induces tumor cell proliferation and migration, and activation and migration of endothelial cells (9)(10)(11). Stimulation of two other known SEMA4D receptors, PLEXIN B-2 (intermediate affinity; expressed on keratinocytes and other cells) and CD72 (lowaffinity; expressed in lymphoid tissue), appears to be involved in epithelial wound repair (12) and regulation of B-cell responses (13), respectively. SEMA4D has both a cellular, membrane-bound form (cSE-MA4D) and a biologically active soluble ligand (sSEMA4D) generated by cleavage of the cellular form (13).…”

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

“…PLXNB2, whose best characterized ligand is SEMA4C, also binds SEMA4D with intermediate affinity. A recent report indicates that PLXNB2 is expressed on keratinocytes and can activate SEMA4D-positive gd T cells to contribute to epithelial wound repair (29). CD72 is a relatively low-affinity (K D ¼ 300 nmol/L) SEMA4D receptor (2) that is expressed primarily on B cells, APCs, and platelets (30).…”