Wendy L. Havran

Characterization of the Murine Antigenic Determinant, Designated L3T4a, Recognized by Monoclonal Antibody GK 1.5: Expression of L3T4a by Functional T Cell Clones Appears to Correlate Primarily with Class II MHC Antigen‐Reactivity

We describe here the properties of mAb GK1.5, which recognizes a cell surface molecule designated L3T4; the determinant on L3T4 recognized by mAb GK1.5 is designated L3T4a. We present evidence here that: i) the expression of L3T4a by murine T cell clones correlates primarily with class II MHC antigen-reactivity; ii) mAb GK1.5 blocks all class II MHC antigen-specific functions (cytolysis, proliferation, release of lymphokines) by murine class II MHC antigen-reactive T cell clones, although there appears to be clonal heterogeneity in the degree to which these functions are blocked by mAb GK1.5; iii) mAb GK1.5 blocks class II MHC antigen-specific release of IL-2 from cloned T cell hybridomas by blocking class II MHC antigen-specific binding; and iv) L3T4 is very similar to the human Leu3/T4 antigen. The properties of mAb GK1.5 (complement fixation, reactivity with all mouse strains tested, profound blocking of all class II MHC antigen-specific functions by murine T cells, usefulness for FACS analyses, and usefulness for immuno-precipitation/SDS-PAGE analyses) make it suitable for investigating both the role of class II MHC antigen-reactive T cells in various immunological phenomena and the mechanistic basis, at the molecular level, of class II MHC antigen-reactivity by murine T cells.

Protection of the intestinal mucosa by intraepithelial gamma delta T cells.

γδ intraepithelial T lymphocytes (IEL) represent a major T cell population within the intestine of unclear functional relevance. The role of intestinal γδ IEL was evaluated in the dextran sodium sulfate (DSS) induced mouse colitis model system. Large numbers of γδ T cells, but not αβ T cells, were localized at sites of DSS-induced epithelial cell damage. γδ IEL in DSS treated mice expressed keratinocyte growth factor (KGF), a potent intestinal epithelial cell mitogen. γδ cell-deficient mice (TCRδ−/−) and KGF-deficient mice (KGF−/−), but not αβ cell-deficient mice (TCRα−/−), were more prone than wild-type mice to DSS-induced mucosal injury and demonstrated delayed tissue repair after termination of DSS treatment. Termination of DSS treatment resulted in vigorous epithelial cell proliferation in wild-type mice but not in TCRδ−/− mice or KGF−/− mice. These results suggest that γδ IEL help preserve the integrity of damaged epithelial surfaces by providing the localized delivery of an epithelial cell growth factor.

Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1

A fine balance between rates of proliferation and apoptosis in the skin provides a defensive barrier and a mechanism for tissue repair after damage. Vγ3+ 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 role for human skin–resident T cells in wound healing

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.

Skin γδ T‐cell functions in homeostasis and wound healing

Summary:  There is a resident population of T cells found in murine skin that expresses an invariant Vγ3Vδ1 T‐cell receptor (TCR), and these cells are significantly different from lymphoid γδ T cells and αβ 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 γδTCR only found in the skin. Skin γδ 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 γδ T cells and keratinocytes that contributes to the maintenance of normal skin and wound healing.

An innate view of γδ T cells

Abstract Findings made during the past few years demonstrate that γδ T cells apparently share with macrophages a propensity to recognize nonpeptidic molecules of the kind most commonly associated with microorganisms and stressed cells. In general, recognition of these antigens by γδ T cells involves the antigen receptor but does not require antigen presenting cells to express MHC gene products or to have a functional antigen processing machinery. Other recent advances continue to support the notion that γδ T cells can perform specialized functions related to the repair of tissue damage.

γδ T cell-induced hyaluronan production by epithelial cells regulates inflammation

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.

A Role for CD81 in Early T Cell Development

Early stages of T cell development are thought to include a series of coordinated interactions between thymocytes and other cells of the thymus. A monoclonal antibody specific for mouse CD81 was identified that blocked the appearance of αβ but not γδ T cells in fetal organ cultures initiated with day 14.5 thymus lobes. In reaggregation cultures with CD81-transfected fibroblasts, CD4−CD8− thymocytes differentiated into CD4+CD8+ T cells. Thus, interactions between immature thymocytes and stromal cells expressing CD81 are required and may be sufficient to induce early events associated with T cell development.

The Junctional Adhesion Molecule JAML Is a Costimulatory Receptor for Epithelial γδ T Cell Activation

Skin Reaction Lymphocytes in the skin known as γδ T cells provide an important barrier against infection and injury. Unlike classical αβ T cells, less is known about the molecular requirements of γδ T cell activation. Two studies demonstrate that the junctional adhesion molecule–like protein (JAML) is a costimulatory molecule for mouse γδ T. Witherden et al. (p. 1205; see the Perspective by Shaw and Huang) showed that JAML, binding to its ligand Coxsackie and adenovirus receptor (CAR), leads to proliferation, as well as cytokine and growth factor production by γδ T cells. In vivo, JAML-CAR interactions contributed to the wound healing response in mice. Verdino et al. (p. 1210; see the Perspective by Shaw and Huang) present a crystal structure of CAR/JAML, which revealed an intracellular signaling motif similar to that known for the αβ T cell costimulatory receptor that signals through phosphoinositide 3-kinase. A costimulatory receptor for immune cells in the skin is identified. γδ T cells present in epithelial tissues provide a crucial first line of defense against environmental insults, including infection, trauma, and malignancy, yet the molecular events surrounding their activation remain poorly defined. Here we identify an epithelial γδ T cell–specific costimulatory molecule, junctional adhesion molecule–like protein (JAML). Binding of JAML to its ligand Coxsackie and adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation leads to diminished γδ T cell activation and delayed wound closure akin to that seen in the absence of γδ T cells. Our results identify JAML as a crucial component of epithelial γδ T cell biology and have broader implications for CAR and JAML in tissue homeostasis and repair.

Epidermal T Cells and Wound Healing

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.