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      Skin‐resident memory T cells as a potential new therapeutic target in vitiligo and melanoma

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          Abstract

          Tissue‐resident memory T (T RM) cells are abundant in the memory T cell pool and remain resident in peripheral tissues, such as the skin, where they act as alarm sensors or cytotoxic killers. T RM cells persist long after the pathogen is eliminated and can respond rapidly upon reinfection with the same antigen. When aberrantly activated, skin‐located T RM cells have a profound role in various skin disorders, including vitiligo and melanoma. Autoreactive T RM cells are present in human lesional vitiligo skin and mouse models of vitiligo, which suggests that targeting these cells could be effective as a durable treatment strategy for vitiligo. Furthermore, emerging evidence indicates that induction of melanoma‐reactive T RM cells is needed to achieve effective protection against tumor growth. This review highlights seminal reports about skin‐resident T cells, focusing mainly on their role in the context of vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases.

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          Most cited references60

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Skin immune sentinels in health and disease.

            Human skin and its immune cells provide essential protection of the human body from injury and infection. Recent studies reinforce the importance of keratinocytes as sensors of danger through alert systems such as the inflammasome. In addition, newly identified CD103(+) dendritic cells are strategically positioned for cross-presentation of skin-tropic pathogens and accumulating data highlight a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology. This Review focuses on recent progress in dissecting the functional role of skin immune cells in skin disease.
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              Memory T cell subsets, migration patterns, and tissue residence.

              Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
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                Author and article information

                Contributors
                tiagoreismatos@gmail.com
                Journal
                Pigment Cell Melanoma Res
                Pigment Cell Melanoma Res
                10.1111/(ISSN)1755-148X
                PCMR
                Pigment Cell & Melanoma Research
                John Wiley and Sons Inc. (Hoboken )
                1755-1471
                1755-148X
                08 July 2019
                September 2019
                : 32
                : 5 ( doiID: 10.1111/pcmr.v32.5 )
                : 612-622
                Affiliations
                [ 1 ] Department of Dermatology and Netherlands Institute for Pigment Disorders Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam Amsterdam Infection & Immunity Institute Amsterdam the Netherlands
                Author notes
                [*] [* ] Correspondence

                Tiago. R. Matos, Department of Dermatology, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

                Email: tiagoreismatos@ 123456gmail.com

                Author information
                https://orcid.org/0000-0003-3376-6734
                https://orcid.org/0000-0002-0800-0721
                https://orcid.org/0000-0003-2864-8207
                Article
                PCMR12803
                10.1111/pcmr.12803
                6851629
                31230406
                e798286b-23b4-49bd-aca3-fe455b759e78
                © 2019 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 October 2018
                : 16 May 2019
                : 14 June 2019
                Page count
                Figures: 4, Tables: 0, Pages: 11, Words: 9729
                Categories
                Review
                Review
                Custom metadata
                2.0
                September 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:13.11.2019

                Dermatology
                autoimmunity,immunology,immunotherapy,melanoma,t lymphocytes,vitiligo
                Dermatology
                autoimmunity, immunology, immunotherapy, melanoma, t lymphocytes, vitiligo

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