Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions (original) (raw)
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The Journal of Immunology, 2010
NKT cells are key regulators of autoimmunity, tumor immune surveillance, and the immune response to pathogens. The role of NKT cells in regulating adaptive immunity to cutaneous Ags is largely unknown. This study explores the role of CD1d-restricted NKT cells in cross-priming of CD8 effector T cells to OVA expressed in epithelial keratinocytes (K5mOVA transgenic mouse). In a skin grafting model, we show that NKT cells enhance the rejection of K5mOVA skin grafts by promoting generation of OVA-specific CD8 effector T cells in the skin-draining lymph nodes. This is associated with a decrease in the proportion of both Th17 cells and IL-17-producing NKT cells within the lymph node, thereby inducing a Th1-biased response by increasing the ratio of IFN-γ to IL-17 production. Administration of a strong agonist ligand (α-galactosylceramide) for NKT cells induced higher levels of local IFN-γ production, enhancing the rate of K5mOVA graft rejection. Thus, NKT cells can promote adaptive immunity to cell-associated Ag expressed in skin by local regulation of IFN-γ production in secondary lymphoid tissue during cross-priming of effector CD8 T cells. Skin integrity is controlled by a complex immunosurveillance network, vital for host survival. Maintaining a balance of active defense mechanisms to clear pathogens and prevent tumor development, and tolerogenic pathways to prevent chronic inflammation and autoimmunity, is critical to achieve immune homeostasis. Th17 cytokines have recently been associated with inflammatory processes in skin (1-3), once attributed solely to Th1 responses. Th1 and Th17 T cells are often colocalized in inflammatory skin environments; however, uncertainty exists in the relative contributions of IFN-γ and IL-17 and whether these cytokines work in synergism or are antagonistic (4-10). NKT cells regulate adaptive immunity to infections, cancer, and autoimmune reactions through production of Th1 (particularly IFN-γ) or Th2 (IL-4, IL-10, IL-13) cytokines, and have been implicated in skin diseases such as atopic dermatitis, psoriasis, and UV-induced skin cancer (reviewed in Ref. 11). Recent reports have provided convincing evidence that NKT cells are also capable of producing Th17 cytokines such as IL-21 (12), IL-22 (13), and IL-17 (14-19). IL-17 production by NKT cells was first characterized in a model of airway neutrophilia, revealing an NK1.1 − IL-17 + NKT subset in lungs (19). Further reports have
Journal of Experimental Medicine, 2002
The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) ␥␦ ϩ (V ␥ 5 ϩ ) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in ␥␦ T cells ( ␦ Ϫ / Ϫ mice), and in ␦ Ϫ / Ϫ mice reconstituted with DETC or with different ␥␦ cell subpopulations. NOD. ␦ Ϫ / Ϫ and FVB. ␦ Ϫ / Ϫ mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6. ␦ Ϫ / Ϫ strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD. ␦ Ϫ / Ϫ mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB. ␦ Ϫ / Ϫ , but not in C57BL/6. ␦ Ϫ / Ϫ mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.  Ϫ / Ϫ ␦ Ϫ / Ϫ mice lacking all T cells, indicating that ␣ T cell-mediated inflammation is the target for ␥␦ -mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant dermatitis in FVB. ␦ Ϫ / Ϫ mice were down-regulated by V ␥ 5 ϩ DETC, but not by epidermal T cells expressing other ␥␦ TCRs. This study demonstrates that functional impairment at an epithelial interface can be specifically attributed to absence of the local TCR-␥␦ ϩ IEL subset and suggests that systemic inflammatory reactions may more generally be subject to substantial regulation by local IELs.
Nature Immunology, 2014
Boundary tissues, including the skin, are continually exposed to foreign antigens, which must be monitored and possibly eliminated. Upon exposure to foreign antigens, skin dendritic cells (DCs), including epidermal Langerhans cells (LCs), capture the antigens and migrate to draining lymph nodes (LNs), where the presentation of antigen to naive T cells occurs mainly in the T cell zone. In this location, the accumulation of naive T cells in the vicinity of DCs is mediated by signaling via the chemokine receptor CCR7 (ref. 1). The T cell zone in the draining LNs facilitates the efficient encounter of antigen-bearing DCs with antigen-specific naive T cells.
The Skin-Resident Immune Network
Current Dermatology Reports, 2013
The skin provides an effective physical and biological barrier against environmental and pathogenic insults whilst ensuring tolerance against commensal microbes. This protection is afforded by the unique anatomy and cellular composition of the skin, particularly the vast network of skin-associated immune cells. These include the longappreciated tissue-resident macrophages, dendritic cells, and mast cells, as well as the more recently described dermal γδ T cells and innate lymphoid cells. Collectively, these cells orchestrate the defense against a wide range of pathogens and environmental challenges, but also perform a number of homeostatic functions. Here, we review recent developments in our understanding of the various roles that leukocyte subsets play in cutaneous immunobiology, and introduce the newer members of the skin immune system. Implications for human disease are discussed.
Journal of Clinical Investigation, 2010
Tregs play an important role in protecting the skin from autoimmune attack. However, the extent of Treg trafficking between the skin and draining lymph nodes (DLNs) is unknown. We set out to investigate this using mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light. By exposing the skin of Kaede-transgenic mice to violet light, we were able to label T cells in the periphery under physiological conditions with Kaede-red and demonstrated that both memory phenotype CD4 + Foxp3non-Tregs and CD4 + Foxp3 + Tregs migrated from the skin to DLNs in the steady state. During cutaneous immune responses, Tregs constituted the major emigrants and inhibited immune responses more robustly than did LN-resident Tregs. We consistently observed that cutaneous immune responses were prolonged by depletion of endogenous Tregs in vivo. In addition, the circulating Tregs specifically included activated CD25 hi Tregs that demonstrated a strong inhibitory function. Together, our results suggest that Tregs in circulation infiltrate the periphery, traffic to DLNs, and then recirculate back to the skin, contributing to the downregulation of cutaneous immune responses. Authorship note: Michio Tomura and Tetsuya Honda contributed equally to this work.
Resident Skin-specific γδ T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation
Journal of Experimental Medicine, 2002
The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) γδ+ (Vγ5+) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in γδ T cells (δ−/− mice), and in δ−/− mice reconstituted with DETC or with different γδ cell subpopulations. NOD.δ−/− and FVB.δ−/− mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6.δ−/− strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD.δ−/− mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB.δ−/−, but not in C57BL/6.δ−/− mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.β−/− δ−/− mice lacking all T cells, indicating that αβ T cell–mediated inflammation is the target for γδ-mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant de...