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Lymphocytes T mémoires et conséquences sur la réponse inflammatoire épidermique et la pigmentation

Abstract : Vitiligo is a depigmenting disorder resulting from the loss of epidermal melanocytes: the cells responsible for melanin production. Vitiligo is a multifactorial disease involving genetic factors, environmental triggers, abnormal melanocyte oxidative and energetic metabolisms and impaired inflammatory and immune response. Recently, we showed that vitiligo skin is defined by the presence of resident memory T cells expressing the chemokine receptor CXCR3, characteristic of a skewed Th1/Tc1 phenotype. The aim of my thesis is to characterize the phenotype and function of vitiligo blood and skin T-cells, and to study the impact of soluble factors produced by skin T-cells on the epidermal inflammatory response and the loss of melanocytes observed during vitiligo. We observed a decreased proportion of blood Th1/Tc1, Th17/Tc17 and Th1/Th17-Tc1/Tc17 effector memory T cell subsets in vitiligo patients compared to healthy donors, suggesting a recruitment of these T-cell subpopulations into the skin of vitiligo patients. Moreover, we showed that vitiligo skin T cells secretome is predominantly defined by the presence of type 1: Interferon-γ (IFNγ) and Tumor Necrosis Factor α (TNFα), but also type-2 cytokines: Interleukin-5 (IL-5) and IL-13, suggesting that vitiligo is not only a Th1/Tc1 skewed immune disease. In addition, soluble factors produced by vitiligo skin T-cells induced an epidermal inflammatory response (involving both keratinocytes and melanocytes) and an alteration of melanocyte energetic and oxidative metabolisms. Soluble factors also induced a defect of melanocyte adhesion caused by the cleavage of E-cadherin by matrix metalloprotease MMP9, released by keratinocytes in response to IFNγ and TNFα. Our data also highlighted the important role of the JAK/STAT pathway in these effects. Finally, the study of the CXCR3/CXCL9-CXCL10 axis in the epidermis was the last aim of my thesis. Indeed, our preliminary data revealed an epidermal expression of CXCR3by both keratinocytes and melanocytes, and IFNγ in combination with TNFα are likely involved in the upregulation of CXCR3 expression in vitiligo patients’ skin. All together, our results bring new insight into the mechanisms involved in melanocyte loss during vitiligo, highlighting the important role of melanocyte in this disease and identify new therapeutic targets.
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Submitted on : Thursday, July 7, 2022 - 1:01:22 AM
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Christina Martins. Lymphocytes T mémoires et conséquences sur la réponse inflammatoire épidermique et la pigmentation. Médecine humaine et pathologie. Université de Bordeaux, 2020. Français. ⟨NNT : 2020BORD0061⟩. ⟨tel-03715925⟩

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