NKG2D Defines a Subset of Skin Effector Memory CD8 T Cells with Proinflammatory Functions in Vitiligo

Jacquemin, Clément; Martins, Christina; Lucchese, Fabienne; Thiolat, Denis; Taı̈eb, Alain; Sénéschal, Julien; Boniface, Katia

doi:10.1016/j.jid.2019.11.013

Cited by 36 publications

(47 citation statements)

References 45 publications

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“…Of note, expression of “stress molecules” like MHC class I chain‐related protein A and B (MICA/MICB) also increases on DC. MICA/MICB might further activate natural killer group 2D receptor expressed by NK cells and a subgroup of cytotoxic αβ T cells like effector memory T cells (T EM ), which might unleash their effector mechanisms, followed by melanocytes being killed and release of autoantigen from dying melanocytes 145 …”

Section: Innate 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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Section: Innate Immune Activationmentioning

confidence: 99%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

126

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“…7 In this regard, we have previously shown that vitiligo perilesional skin is imprinted with CD8 + T cells expressing CXCR3, characterized by a resident memory phenotype and production of elevated levels of both IFN-c and TNF-a. 8,9 Moreover, we demonstrated a major role of IFN-a, mainly produced by plasmacytoid dendritic cells in vitiligo skin, in the upregulated production of CXCL9 and CXCL10 by keratinocytes, 10,11 leading to the recruitment of CXCR3 + T cells into the skin.…”

mentioning

confidence: 75%

“…Functional studies in disease‐prone mouse models have further emphasized the critical role of a Th1/Tc1 cytokine signature with the involvement of the IFN‐γ‐dependent chemokine ligands CXCL9 and CXCL10, associated with the recruitment of T cells expressing their cognate receptor CXCR3 7. In this regard, we have previously shown that vitiligo perilesional skin is imprinted with CD8 + T cells expressing CXCR3, characterized by a resident memory phenotype and production of elevated levels of both IFN‐γ and TNF‐α 8,9. Moreover, we demonstrated a major role of IFN‐α, mainly produced by plasmacytoid dendritic cells in vitiligo skin, in the upregulated production of CXCL9 and CXCL10 by keratinocytes,10,11 leading to the recruitment of CXCR3 + T cells into the skin.…”

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confidence: 99%

Phenotype and function of circulating memory T cells in human vitiligo*

et al. 2020

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Summary Background Vitiligo is a chronic inflammatory skin disorder characterized by the loss of melanocytes. While a T helper cell (Th)1/cytotoxic T cell (Tc)1‐skewed immune response is now well demonstrated in vitiligo, recent data suggest that the T‐cell component could be more complex, involving different combinatorial T‐cell subsets. Objectives To analyse the phenotype and function of circulating CD4+ and CD8+ memory T‐cell subsets in patients with stable and active vitiligo, in comparison with patients with psoriasis and healthy controls. Methods This is a monocentric, prospective, descriptive and exploratory study. Multiparametric flow cytometry analyses were performed to evaluate the surface expression of homing and T‐cell‐subset markers together with intracellular cytokine production in peripheral blood mononuclear cells from 60 patients with vitiligo, 25 patients with psoriasis and 28 healthy donors. Results Vitiligo peripheral blood circulating effector and central memory T cells expressed similar proportions of skin‐homing markers. Decrease in the frequencies of circulating CD4+ and CD8+ Th1/Tc1, Th17/Tc17, and Th1/Th17 or Tc1/Tc17 effector memory T‐cell subsets were observed in patients with vitiligo compared with healthy donors. Similar observations were made in psoriasis. In contrast, vitiligo circulating T cells showed a similar capacity for proinflammatory cytokine production compared with those in psoriasis and healthy controls. Conclusions The decreased frequencies of circulating Th1/Tc1, Th17/Tc17 and Th1/Th17–Tc1/Tc17 cells suggest a possible migration of these T‐cell subsets into the skin of patients with vitiligo. These could be targeted to prevent flares of the disease. What is already known about this topic? Vitiligo is a chronic inflammatory skin disorder associated with the loss of melanocytes. Vitiligo is characterized by a T helper cell (Th)1/cytotoxic T cell (Tc)1‐skewed immune response in the skin. What does this study add? A thorough analysis of the phenotype and function of circulating memory T cells suggests the migration of Th1/Tc1, Th17/Tc17 and Th1/Th17–Tc1/Tc17 cell subsets in the skin. What is the translational message? A better understanding of the different immune T‐cell subsets involved in vitiligo could lead to better therapeutic options. Linked Comment: Matos. Br J Dermatol 2020; 183:803.

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“…Recently, NKG2D, an activating receptor, was found to define a highly functional memory CD8 T-cell subset in vitiliginous skin and could therefore represent a potential therapeutic target. A monoclonal antibody directed against NKG2D showed promising results in Crohn's disease, supporting further development in this disease, but also in other chronic inflammatory disease where NKG2D-expressing cells are involved [44,45].…”

Section: T Helper Type 1-skewed Immune Profile In Vitiligomentioning

confidence: 89%

Vitiligo, From Physiopathology to Emerging Treatments: A Review

Migayron

Boniface

Sénéschal

2020

Dermatol Ther (Heidelb)

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Vitiligo is a chronic inflammatory skin disease leading to the loss of epidermal melanocytes. To date, treatment options for vitiligo patients are limited, lack sustained efficacy, and are mainly based on off-label use of immunosuppressive agents, such as systemic or topical steroids or topical calcineurin inhibitors, in association with the use of ultraviolet light. However, recent insights into the understanding of the immune pathogenesis of the disease have led to the identification of several therapeutic targets and the development of targeted therapies that are now being tested in clinical trials. In this review, based on the physiopathology of the disease, we summarize emerging targets that could be developed for the treatment of vitiligo and discuss recent and ongoing developments of drugs for the management of the disease.

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NKG2D Defines a Subset of Skin Effector Memory CD8 T Cells with Proinflammatory Functions in Vitiligo

Cited by 36 publications

References 45 publications

Mechanisms of melanocyte death in vitiligo

Mechanisms of melanocyte death in vitiligo

Phenotype and function of circulating memory T cells in human vitiligo*

Vitiligo, From Physiopathology to Emerging Treatments: A Review

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