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

Willemsen, Marcella; Linkutė, Rugile; Luiten, Rosalie M.; Matos, Tiago R.

doi:10.1111/pcmr.12803

Cited by 30 publications

(31 citation statements)

References 96 publications

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“…Furthermore, skin resident memory T cells also play a protective role in skin infection, such as HSV ( 35 ), C. albicans ( 12 ), leishmania major ( 13 ), and in skin cancers, such as melanoma ( 126 ) and squamous cell carcinoma ( 127 ). They also play a pathogenic role in some autoinflammatory skin diseases; vitiligo ( 9 , 128 ), psoriasis ( 8 ) and alopecia areata ( 10 ). Thus, the vaccination-induced T RM cell strategy may also have a potential to become a novel therapeutic approach to protect the skin from infection, prevent tumor growth, or suppress autoreactive immune responses.…”

Section: Skin T Rm Cells In Cutaneous Defense Systmentioning

confidence: 99%

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Pathophysiology of Skin Resident Memory T Cells

et al. 2021

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Tissue resident memory T (TRM) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin TRM cells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8+CD69+CD103+ TRM cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-β are required for the formation of long-lived TRM cell population in skin. Skin TRM cells engage virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. Secondary TRM cell populations are derived from pre-existing TRM cells and newly recruited TRM precursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8+ TRM cells at challenged site. Skin TRM cells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these TRM cells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8+CD103+CD49a- TRM cells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8+CD103+CD49a+ TRM cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin TRM cells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8+ TRM cells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed TRM cells. CD8+ CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8+ TRM cells. This review will discuss the current understanding of skin TRM biology and their contribution to skin homeostasis and diseases.

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Section: Skin T Rm Cells In Cutaneous Defense Systmentioning

confidence: 99%

“…When aberrantly activated, skin T RM cells have a profound role in vitiligo and melanoma ( 128 ). CD8 + CD103 + CD69 + CD49a + T RM cells serve as CTLs ( 74 , 143 ).…”

Section: Skin T Rm Cells In Vitiligomentioning

confidence: 99%

Pathophysiology of Skin Resident Memory T Cells

et al. 2021

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“…According to the expression of the homing receptors and migratory patterns, memory cells protecting human skin are parsed into four subgroups, which were labeled central memory T cells (T CM ), T EM , migratory memory T cells, and T RM 174,175 . Canonical surface markers of CD69 (a T cell activation marker), CD103 (integrin α E ) and CD49a (α‐subunit of the α1β1 integrin receptor) are frequently utilized to distinguish epidermal T RM from circulating memory cells.…”

Section: Adaptive Immune Activationmentioning

confidence: 99%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

126

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Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome‐wide associated studies have identified single‐nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte‐specific antigens exposure. Of note, the self‐responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type‐1‐skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8+ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well‐established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.

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“…Of interest, skin-resident memory T cell responses to MM are generated naturally as a result of autoimmune vitiligo [ 125 ]. In the epidermis, TRM mediate anti-tumor immunity and promote an MM-immune equilibrium [ 125 , 126 ]. Patients with high intratumoral CD8+ T cells display a higher response to BRAF or BRAF/MEK inhibitors [ 127 ].…”

Section: Exosome-mediated Mir-21 Transportmentioning

confidence: 99%

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

Melnik

John

Carrera-Bastos

et al. 2020

Cancers

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DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.

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

Cited by 30 publications

References 96 publications

Pathophysiology of Skin Resident Memory T Cells

Pathophysiology of Skin Resident Memory T Cells

Mechanisms of melanocyte death in vitiligo

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

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