Intraepithelial γδ T lymphocytes (γδ IEL) have important roles in repair of tissue damage at epithelial sites, such as skin and intestine. Molecules that orchestrate these γδ T-cell functions are not well defined. Recently, interaction of the semaphorin CD100 on skin γδ T cells with plexin B2 on keratinocytes was shown to be important for effective γδ T-cell function in the epidermis, which raised the possibility that CD100 may exert similar functions in the intestinal tract. In this study, we find that CD100 is expressed on all IEL, and plexin B2 is present on all epithelial cells of the mouse colon. Using the dextran sulfate sodium (DSS) mouse model of colitis, disease severity is significantly exacerbated in CD100-deficient (CD100−/−) mice, with increased colon ulceration and mucosal infiltration with inflammatory cells. The severe colitis in CD100−/− mice is attributable to the failure of the colon epithelium to mount a proliferative response to damage. Unlike wild-type γδ IEL, γδ IEL from CD100−/− mice fail to produce keratinocyte growth factor-1 (KGF-1) in response to DSS treatment. Administration of recombinant KGF-1 to CD100−/− animals ameliorates disease and reverses colitis susceptibility. These results demonstrate that CD100-mediated signals are critical for effective activation of γδ IEL to produce growth factors, including KGF-1, that are required for healing of the colon epithelium during colitis.

The murine epidermis contains resident T cells that express a canonical γδ TCR and arise from fetal thymic precursors. These cells are termed dendritic epidermal T cells (DETC) and use a TCR that is restricted to the skin in adult animals. DETC produce low levels of cytokines and growth factors that contribute to epidermal homeostasis. Upon activation, DETC can secrete large amounts of inflammatory molecules which participate in the communication between DETC, neighboring keratinocytes and langerhans cells. Chemokines produced by DETC may recruit inflammatory cells to the epidermis. In addition, cell–cell mediated immune responses also appear important for epidermal–T cell communication. Information is provided which supports a crucial role for DETC in inflammation, wound healing, and tumor surveillance.

A fine balance between rates of proliferation and apoptosis in the skin provides a defensive barrier and a mechanism for tissue repair after damage. V3+ dendritic epidermal T cells (DETCs) are primary modulators of skin immune responses. Here we show that DETCs both produce and respond to insulin-like growth factor 1 (IGF-1) after T cell receptor stimulation. Mice deficient in DETCs had a notable increase in epidermal apoptosis that was abrogated by the addition of DETCs or IGF-1. Furthermore, DETC-deficient mice had reduced IGF-1 receptor activation at wound sites. These findings indicate critical functions for DETC-mediated IGF-1 production in regulating skin homeostasis and repair.

γδ T cells lie at the interface between innate and adaptive immunity, sharing features with both arms of the immune system. The vast majority of γδ T cells reside in epithelial layers of tissues such as skin, gut, lung, tongue and reproductive tract where they provide a first line of defense against environmental attack. The existence of epithelium-resident γδ T cells has been known for over 20 years but our understanding of the molecular events regulating development and function of these cells is incomplete. We review recent advances in the field, with particular emphasis on the γδ T cell population resident in mouse epidermis. These studies have enhanced our knowledge and understanding of the life cycle of this enigmatic population of cells.

γδ T cells respond rapidly to keratinocyte damage, providing essential contributions to the skin wound healing process. The molecular interactions regulating their response are unknown. Here, we identify a role for interaction of plexin B2 with 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. 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.Highlights► Plexin B2 is a functional ligand for CD100 in mouse skin ► Plexin B2-CD100 interaction is required for epidermal γδ T cell activation ► CD100 ligation induces cellular rounding ► Plexin B2-CD100 interaction delivers signals through ERK and cofilin