[Show abstract][Hide abstract] ABSTRACT: TCR-specific activation is pivotal to dendritic epidermal T cell (DETC) function during cutaneous wound repair. However, DETC TCR ligands are uncharacterized, and little is known about their expression patterns and kinetics. Using soluble DETC TCR tetramers, we demonstrate that DETC TCR ligands are not constitutively expressed in healthy tissue but are rapidly upregulated following wounding on keratinocytes bordering wound edges. Ligand expression is tightly regulated, with downmodulation following DETC activation. Early inhibition of TCR-ligand interactions using DETC TCR tetramers delays wound repair in vivo, highlighting DETC as rapid responders to injury. To our knowledge, this is the first visualization of DETC TCR ligand expression, which provides novel information about how ligand expression impacts early stages of DETC activation and wound repair.
The Journal of Immunology 03/2012; 188(7):2972-6. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity and related type 2 diabetes are increasing at epidemic proportions globally. It is now recognized that inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. This review will focus specifically on the impact of obesity on γδ T cells, a T-cell subset that is found in high concentrations in epithelial tissues such as the skin, intestine, and lung. Epithelial γδ T cell function is of particular concern in obesity as they are the guardians of the epithelial barrier and mediate repair. A breakdown in their function, and subsequently the deterioration of the epithelium can result in dire consequences for the host. Obese patients are more prone to non-healing injuries, infection, and disease. The resulting inflammation from these pathologies further perpetuates the disease condition already present in obese hosts. Here we will provide insight into the immunomodulation of γδ T cells that occurs in the epithelial barrier during obesity and discuss current therapeutic options.
Immunologic Research 12/2011; 52(3):182-99. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Skin complications and chronic non-healing wounds are common in obesity, metabolic disease, and type 2 diabetes. Epidermal γδ T cells normally produce keratinocyte growth factors, participate in wound repair, and are necessary for keratinocyte homeostasis. We have determined that in γδ T cell-deficient mice, there are reduced numbers of keratinocytes and the epidermis exhibits a flattened, thinner structure with fewer basal keratinocytes. This is important in obesity, where skin-resident γδ T cells are reduced and rendered dysfunctional. Similar to γδ T cell-deficient mice, keratinocytes are reduced and the epidermal structure is altered in two obese mouse models. Even in regions where γδ T cells are present, there are fewer keratinocytes in obese mice, indicating that dysfunctional γδ T cells are unable to regulate keratinocyte homeostasis. The impact of absent or impaired γδ T cells on epidermal structure is exacerbated in obesity as E-cadherin localization and expression are additionally altered. These studies reveal that γδ T cells are unable to regulate keratinocyte homeostasis in obesity and that the obese environment further impairs skin structure by altering cell-cell adhesion. Together, impaired keratinocyte homeostasis and epidermal barrier function through direct and indirect mechanisms result in susceptibility to skin complications, chronic wounds, and infection.
Journal of Investigative Dermatology 08/2011; 131(12):2409-18. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epithelial cells provide an initial line of defense against damage and pathogens in barrier tissues such as the skin; however this balance is disrupted in obesity and metabolic disease. Skin gammadelta T cells recognize epithelial damage, and release cytokines and growth factors that facilitate wound repair. We report here that hyperglycemia results in impaired skin gammadelta T cell proliferation due to altered STAT5 signaling, ultimately resulting in half the number of gammadelta T cells populating the epidermis. Skin gammadelta T cells that overcome this hyperglycemic state are unresponsive to epithelial cell damage due to chronic inflammatory mediators, including TNFalpha. Cytokine and growth factor production at the site of tissue damage was partially restored by administering neutralizing TNFalpha antibodies in vivo. Thus, metabolic disease negatively impacts homeostasis and functionality of skin gammadelta T cells, rendering host defense mechanisms vulnerable to injury and infection.
PLoS ONE 07/2010; 5(7):e11422. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The murine epidermis contains resident T cells that express a canonical gammadelta 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 gammadelta 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 gammadelta 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 Journal of Immunology 05/2010; 184(10):5423-8. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The major gammadelta T cell subset in the human peripheral blood expresses the Vgamma9delta2 TCR and recognizes non-peptidic prenyl pyrophosphate antigens such as isopentylpyrophosphate (IPP). Upon activation the gammadelta T cells rapidly secrete antiviral cytokines similar to classical memory alphabeta T cells. Here we have investigated the ability of gammadelta T lymphocytes from human PBMC to become activated by influenza A virus infection. Vgamma9Vdelta2 T lymphocytes rapidly upregulate expression of CD25 and CD69 and produce IFN-gamma following influenza infection of PBMC. Moreover, the recognition is cross-reactive between various subtypes of influenza, but not with vaccinia virus. Vgamma9Vdelta2 T cell responses are potently reduced by the HMG-CoA reductase inhibitor mevastatin, which inhibits the mevalonate pathway and IPP synthesis. Our results indicate that influenza virus infection induces the rapid activation and function of Vgamma9Vdelta2 T lymphocytes in the peripheral blood via a mechanism that depends on the mevalonate pathway.
[Show abstract][Hide abstract] ABSTRACT: 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 alphabeta(+) and gammadelta(+) 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 alphabeta(+) and Vdelta1(+) 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.
Journal of Experimental Medicine 04/2009; 206(4):743-50. · 13.91 Impact Factor
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[Show abstract][Hide abstract] ABSTRACT: The mammalian target of rapamycin (mTOR) signaling pathway integrates signals from the environment to the nucleus for the regulation of cellular growth, metabolism and survival. Lymphocytes frequently rely on this pathway, but it is carefully regulated through the reception of signals via cytokine, growth factor and co-stimulatory receptors. Recent studies have begun to elucidate why T cell subsets rely on this pathway to varying degrees. Ultimately these findings will help distinguish the parameters that guide T cell homeostasis and activation-induced function between the different T cell populations. The mTOR pathway has been the focus of many immunosuppressive and cancer treatment regimens, therefore there is a great need to understand the impact of suppression not only on the T cell populations targeted, but on bystander T cells as well.
[Show abstract][Hide abstract] ABSTRACT: Disruptions in the normal program of tissue repair can result in poor wound healing, which perturbs the integrity of barrier tissues such as the skin. Such defects in wound repair occur in transplant recipients treated with the immunosuppressant drug rapamycin (sirolimus). Intraepithelial lymphocytes, such as gammadelta T cells in the skin, mediate tissue repair through the production of cytokines and growth factors. The capacity of skin-resident T cells to function during rapamycin treatment was analyzed in a mouse model of wound repair. Rapamycin treatment renders skin gammadelta T cells unable to proliferate, migrate, and produce normal levels of growth factors. The observed impairment of skin gammadelta T cell function is directly related to the inhibitory action of rapamycin on mammalian target of rapamycin. Skin gammadelta T cells treated with rapamycin are refractory to IL-2 stimulation and attempt to survive in the absence of cytokine and growth factor signaling by undergoing autophagy. Normal wound closure can be restored in rapamycin-treated mice by addition of the skin gammadelta T cell-produced factor, insulin-like growth factor-1. These studies not only reveal that mammalian target of rapamycin is a master regulator of gammadelta T cell function but also provide a novel mechanism for the increased susceptibility to nonhealing wounds that occurs during rapamycin administration.
The Journal of Immunology 10/2008; 181(6):3974-83. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Among 17 HLA-A2-positive healthy adults, CD8+ T-cell responses against an HLA-A2-restricted matrix protein 1 (M1) epitope increased after immunization with trivalent inactivated influenza vaccine (TIV) in two individuals. The presence of M1 in TIV was confirmed by Western blotting. T-cell cytotoxicity assays showed that TIV is processed and the epitope is presented by antigen-presenting cells to an M1 epitope-specific CD8+ T-cell line for specific lysis. These data show that TIV, which is formulated to contain surface glycoproteins to induce serotype-specific antibody responses, also contains M1, capable of inducing subtype cross-reactive CD8+ T-cell responses in some vaccinees.
Journal of Virology 08/2008; 82(18):9283-7. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Intraepithelial gammadelta-T cells are present in all epithelial tissues, where they reside in close contact with neighboring epithelial cells. Our data support the idea that the role of these cells is to monitor neighboring cells for signs of damage or disease. Once a problem is detected, the intraepithelial gammadelta-T cells can lyse damaged or malignant epithelial cells, directly participate in tissue repair through production of epithelial growth factors, and play a unique role in the recruitment of inflammatory cells to the site of damage. Intraepithelial gammadelta-T cells play unique roles in homeostasis and disease.
[Show abstract][Hide abstract] ABSTRACT: 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 gammadelta T cells play specialized roles in keratinocyte proliferation during wound repair. Here, we show that gammadelta 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 gammadelta 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 gammadelta T cells in inflammation and provide a new perspective on T cell regulation of ECM molecules.
Journal of Experimental Medicine 05/2005; 201(8):1269-79. · 13.91 Impact Factor
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[Show abstract][Hide abstract] ABSTRACT: Although gammadelta T cells compose a small proportion of lymphocytes in lymphoid compartments and peripheral blood, they are the major T-cell population present in epithelial tissues. However, the role played by gammadelta TCR expressing intraepithelial lymphocytes (IEL) has been enigmatic. The location of tissue-resident IEL suggests that they are important members of the first line of defense against insult for organs exposed to the environment, including the skin, gut, lungs, and reproductive system. Dendritic epidermal T cells (DETC) are the skin-resident gammadeltaIEL and serve as a model system for gammadeltaIEL in other locations. DETC have demonstrated importance in the modulation of immune responses, surveillance and repair of tissue, and resistance to infection. This work discusses recent developments in understanding DETC activation.
Critical Reviews in Immunology 02/2005; 25(1):1-18. · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Although innate T lymphocytes such as gamma delta T cells have been extensively studied, their biological role has remained an enigma to researchers for many years. However, recent advances have begun to explain their complex role in the immune system. Gamma delta T cells are often the major T cell population in epithelial tissues such as the skin, gut, and lung where they have been implicated in maintaining tissue integrity, defending against pathogens, and regulating inflammation. The gamma delta T cells that reside in the skin are a prototypical intra-epithelial lymphocyte (IEL) population. These skin gamma delta T cell receptor (TCR)-expressing cells are named dendritic epidermal T cells (DETC) for their unique dendritic morphology. Using their gamma delta TCR, DETC recognize an unknown ligand expressed by stressed or damaged keratinocytes. Activated DETC exhibit effector functions such as cytokine production, cytolysis, and proliferation in vitro. Recent findings have shown that upon activation by damaged keratinocytes, DETC produce a key keratinocyte growth factor for wound repair called fibroblast growth factor 7 (FGF-7). FGF-7 is produced in vitro and in vivo, suggesting that DETC might play an important role in the biological function of wound repair. Indeed a delay in wound closure and a decrease in the proliferation of keratinocytes at the wound site have been observed in mice lacking gamma delta T cells. In addition to effector functions attributed to DETC, it has also been suggested that gamma delta T cells such as DETC have regulatory roles such as initiating or inhibiting inflammation. This is supported by the findings that DETC produce chemokines and cytokines. Control of the inflammatory response in the epithelium may provide another mechanism to reestablish homeostasis after a biological insult such as wound infliction. Understanding the function of DETC may be useful in the development of future therapies for chronic wounds and the maintenance of skin homeostasis.
Frontiers in Bioscience 10/2004; 9:2640-51. · 4.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A unique population of T lymphocytes, designated dendritic epidermal T cells (DETC), homes to the murine epidermis during fetal development. DETC express a canonical gammadelta TCR, Vgamma3/Vdelta1, 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 TCRdelta(-/-) mouse. Unlike previous reports in which the TCRdelta(-/-) skin was found to be devoid of any DETC, we discovered that TCRdelta(-/-) mice have alphabeta TCR-expressing DETC with a polyclonal Vbeta chain repertoire. The alphabeta DETC are not retained over the life of the animal, suggesting that the gammadelta TCR is critical for the maintenance of DETC in the skin. Although the alphabeta 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.
The Journal of Immunology 04/2004; 172(6):3573-9. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gammadelta T lymphocytes and CD1d-restricted natural killer T cells are classified as innate T lymphocytes, which perform effector functions that protect from malignancy and maintain tissue integrity. Innate T cells also play important regulatory roles in autoimmunity, inflammation and infection. Recent advances have established innate T cells as both effectors and regulators of disease in biological models.
Current Opinion in Immunology 07/2003; 15(3):349-53. · 7.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.