Gammadelta T cell receptor-bearing dendritic epidermal T cells (DETCs) found in murine skin recognize antigen expressed by damaged or stressed keratinocytes. Activated DETCs produce keratinocyte growth factors (KGFs) and chemokines, raising the possibility that DETCs play a role in tissue repair. We performed wound healing studies and found defects in keratinocyte proliferation and tissue reepithelialization in the absence of wild-type DETCs. In vitro skin organ culture studies demonstrated that adding DETCs or recombinant KGF restored normal wound healing in gammadelta DETC-deficient skin. We propose that DETCs recognize antigen expressed by injured keratinocytes and produce factors that directly affect wound repair.

Epidermal T cells have been shown to play unique roles in tissue homeostasis and repair in mice through local secretion of distinct growth factors in the skin. Human epidermis contains both αβ+ and γδ+ T cells whose functional capabilities are not understood. We demonstrate that human epidermal T cells are able to produce insulin-like growth factor 1 (IGF-1) upon activation and promote wound healing in a skin organ culture model. Moreover, an analysis of the functional capabilities of T cells isolated from acute versus chronic wounds revealed a striking difference. Both αβ+ and Vδ1+ T cells isolated from acute wounds actively produced IGF-1, demonstrating that they are activated during tissue damage to participate in wound repair. In contrast, IGF-1 production could not be detected in T cells isolated from chronic wounds. In fact, skin T cells isolated from chronic wounds were refractory to further stimulation, suggesting an unresponsive state. Collectively, these results define a novel role for human epidermis–resident T cells in wound healing and provide new insight into our understanding of chronic wound persistence.

A fine balance between rates of proliferation and apoptosis in the skin provides a defensive barrier and a mechanism for tissue repair after damage. Vgamma3(+) 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.

A unique population of T lymphocytes, designated dendritic epidermal T cells (DETC), homes to the murine epidermis during fetal development. DETC express a canonical γδ TCR, Vγ3/Vδ1, which recognizes Ag expressed on damaged, stressed, or transformed keratinocytes. Recently, DETC were shown to play a key role in the complex process of wound repair. To examine the role of the DETC TCR in DETC localization to the epidermis, maintenance in the skin, and activation in vivo, we analyzed DETC in the TCRδ−/− mouse. Unlike previous reports in which the TCRδ−/− skin was found to be devoid of any DETC, we discovered that TCRδ−/− mice have αβ TCR-expressing DETC with a polyclonal Vβ chain repertoire. The αβ DETC are not retained over the life of the animal, suggesting that the γδ TCR is critical for the maintenance of DETC in the skin. Although the αβ DETC can be activated in response to direct stimulation, they do not respond to keratinocyte damage. Our results suggest that a keratinocyte-responsive TCR is necessary for DETC activation in response to keratinocyte damage and for DETC maintenance in the epidermis.

There is a resident population of T cells found in murine skin that expresses an invariant Vgamma3Vdelta1 T-cell receptor (TCR), and these cells are significantly different from lymphoid gammadelta T cells and alphabeta T cells in terms of ontogeny, tissue tropism, and antigen receptor diversity. These dendritic epidermal T cells are derived from fetal thymic precursor cells, are in constant contact with neighboring epidermal cells, and express a monoclonal gammadeltaTCR only found in the skin. Skin gammadelta T cells have been shown to play unique roles in tissue homeostasis and during tissue repair through local secretion of distinct growth factors including keratinocyte growth factors and insulin-like growth factor-1. In this review, we discuss evidence supporting a role for cross talk between skin gammadelta T cells and keratinocytes that contributes to the maintenance of normal skin and wound healing.

Nonhealing wounds are a major complication of diseases such as diabetes and rheumatoid arthritis. For efficient tissue repair, inflammatory cells must infiltrate into the damaged tissue to orchestrate wound closure. Hyaluronan is involved in the inflammation associated with wound repair and binds the surface of leukocytes infiltrating damaged sites. Skin γδ T cells play specialized roles in keratinocyte proliferation during wound repair. Here, we show that γδ T cells are required for hyaluronan deposition in the extracellular matrix (ECM) and subsequent macrophage infiltration into wound sites. We describe a novel mechanism of control in which γδ T cell–derived keratinocyte growth factors induce epithelial cell production of hyaluronan. In turn, hyaluronan recruits macrophages to the site of damage. These results demonstrate a novel function for skin γδ T cells in inflammation and provide a new perspective on T cell regulation of ECM molecules.

The murine epidermis contains resident T cells that express a canonical γδ TCR. These cells arise from fetal thymic precursors and use a TCR that is restricted to the skin in adult animals. These cells assume a dendritic morphology in normal skin and constitutively produce low levels of cytokines that contribute to epidermal homeostasis. When skin is wounded, an unknown Ag is expressed on damaged keratinocytes. Neighboring γδ T cells then round up and contribute to wound healing by local production of epithelial growth factors and inflammatory cytokines. In the absence of skin γδ T cells, wound healing is impaired. Similarly, epidermal T cells from patients with healing wounds are activated and secreting growth factors. Patients with nonhealing wounds have a defective epidermal T cell response. Information gained on the role of epidermal-resident T cells in the mouse may provide information for development of new therapeutic approaches to wound healing.

The development of intestinal permeability and the penetration of microbial products are key factors associated with the onset of metabolic disease. However, the mechanisms underlying this remain unclear. Here we show that, unlike liver or adipose tissue, high fat diet (HFD)/obesity in mice does not cause monocyte/macrophage infiltration into the intestine or pro-inflammatory changes in gene expression. Rather HFD causes depletion of intestinal eosinophils associated with the onset of intestinal permeability. Intestinal eosinophil numbers were restored by returning HFD fed mice to normal chow and were unchanged in leptin-deficient (Ob/Ob) mice, indicating that eosinophil depletion is caused specifically by a high fat diet and not obesity per se. Analysis of different aspects of intestinal permeability in HFD fed and Ob/Ob mice shows an association between eosinophil depletion and ileal paracelullar permeability, as well as leakage of albumin into the feces, but not overall permeability to FITC dextran. These findings provide the first evidence that a high fat diet causes intestinal eosinophil depletion, rather than inflammation, which may contribute to defective barrier integrity and the onset of metabolic disease.