Human Epidermal Langerhans Cells Maintain Immune Homeostasis in Skin by Activating Skin Resident Regulatory T Cells

Department of Dermatology/Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
Immunity (Impact Factor: 21.56). 05/2012; 36(5):873-84. DOI: 10.1016/j.immuni.2012.03.018
Source: PubMed


Recent studies have demonstrated that the skin of a normal adult human contains 10-20 billion resident memory T cells, including various helper, cytotoxic, and regulatory T cell subsets, that are poised to respond to environmental antigens. Using only autologous human tissues, we report that both in vitro and in vivo, resting epidermal Langerhan cells (LCs) selectively and specifically induced the activation and proliferation of skin resident regulatory T (Treg) cells, a minor subset of skin resident memory T cells. In the presence of foreign pathogen, however, the same LCs activated and induced proliferation of effector memory T (Tem) cells and limited Treg cells' activation. These underappreciated properties of LCs, namely maintenance of tolerance in normal skin, and activation of protective skin resident memory T cells upon infectious challenge, help clarify the role of LCs in skin.

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    • "The herein identified role of DIRC-expressed PD-1 in Treg induction resembles the established role of T cellular PD-1 in Treg induction via PD-1:PD-L1 signaling interactions (Francisco et al., 2009; Wang et al., 2008). Because Tregs represent dominant mediators of immune homeostasis (Hogquist et al., 2005), including in the skin (Dudda et al., 2008), our discovery of functional PD-1 expression by DIRCs supports the existence of a dermal mechanism, in addition to a previously demonstrated epidermal, Langerhans cell-mediated mechanism (Seneschal et al., 2012), of Treg maintenance in mammalian skin. This finding is of current clinical relevance also to human cancer, where PD-1 has evolved as a highly promising target for tumor immunotherapy, with recently completed clinical trials demonstrating objective response rates markedly exceeding those achieved with alternative immunotherapeutic regimens in patients with advanced disease (Postow et al., 2015). "
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    Cell Reports 08/2015; 12(10). DOI:10.1016/j.celrep.2015.08.010 · 8.36 Impact Factor
    • "Promoting oncogenetic alterations, e.g., RAS (Daya-Grosjean et al., 1993) and NOTCH (Durinck et al., 2011), may result from continued UV exposure, immune influences, and other stimuli that drive keratinocyte (KC) proliferation, dedifferentiation , transformation, and ultimately tumor outgrowth (reviewed in Epstein, 1983; Kripke, 1984). Situated adjacent to basal and folliculo-infundibullar KCs that give rise to actinic keratoses and SCC neoplasia is a network of dendritic CD207+ (Langerin+) intraepidermal Langerhans cells (LCs) that (1) survey the epidermis (Nishibu et al., 2006) for evidence of toxin/microbial penetration (Kubo et al., 2009) and (2) serve as antigen-presenting cells for the activation T cells resident in the skin (Seneschal et al., 2012) or after migration to draining lymph nodes (Kaplan et al., 2005; Bobr et al., 2012). "
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    ABSTRACT: Ultraviolet B (UVB) light is considered the major environmental inducer of human keratinocyte DNA mutations, including within the tumor-suppressor gene p53, and chronic exposure is associated with cutaneous squamous cell carcinoma (SCC) formation. Langerhans cells (LC) comprise a dendritic network within the suprabasilar epidermis, yet the role of LC in UVB-induced carcinogenesis is largely unknown. Herein, we show that LC-intact epidermis develops UVB-induced tumors more readily than LC-deficient epidermis. While levels of epidermal cyclopyrimidine dimers (CPD) following acute UVB exposure are equivalent in the presence or absence of LC, chronic UVB-induced p53 mutant clonal islands expand more readily in association with LC which remain largely intact and are preferentially found in proximity to the expanding mutant keratinocyte populations. The observed LC facilitation of mutant p53 clonal expansion is completely αβ and γδ T-cell independent, and is associated with increased intraepidermal expression of interleukin (IL)-22 and the presence of group 3 innate lymphoid cells (ILC3). These data demonstrate that LC play a key role in UVB-induced cutaneous carcinogenesis, and suggest that LC locally stimulate keratinocyte proliferation and innate immune cells that provoke tumor outgrowth.Journal of Investigative Dermatology accepted article preview online, 08 June 2015. doi:10.1038/jid.2015.207.
    Journal of Investigative Dermatology 06/2015; DOI:10.1038/jid.2015.207 · 7.22 Impact Factor
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    • "T cells, rather than T regulatory (T reg) cells in the skin upon activation (Seneschal et al., 2012). Although in the human these DCs play a critical role in immunity, the relevance of LCs to CD8 + T cell–mediated immunity in mice is still disputed . "

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