Compartmentalisation of the immune response in human skin : cross-talk between dendritic cells and T cells in healthy conditions and in psoriasis

Abstract

Human skin is highly compartmentalised and distinct subsets of dendritic cells (DCs) and T cells reside in epidermis and dermis. Alterations in the composition of DCs and T cells have been observed in psoriasis, a common cytokine-driven focal inflammatory skin disease. In this thesis we explore the functional profile of epidermal and dermal DCs and T cells in different phases of psoriasis, and how different cytokines present in homeostasis and inflammation affect the development of tissue resident memory T (Trm) cells.

PAPER I: In lesional psoriasis, langerin-DCs accumulated in the epidermis. Both Langerhans cells (LCs) and epidermal DCs (eDCs) displayed upregulated pro-inflammatory genes and produced IL-23 after stimulation with ligands binding to toll-like receptor (TLR) 4 or 7/8. Elevated gene expression of IL23A and IL15 in LCs combined with their capacity to produce IL-23 upon TLR 7/8 stimulation suggested that LCs maintained their pro-inflammatory profile in resolved psoriasis.

PAPER II: Granzymes (Gzms) and perforin are produced by cytotoxic T cells. Here we show that epidermal T cells produced GzmA in absence of perforin within psoriatic lesions. IL-17-stimulated human keratinocytes, in presence of GzmA, upregulated the production of CXCL1, CXCL12 and CCL4, involved in neutrophil and lymphocyte recruitment, therefore highlighting a new pathway of T cell driven recruitment of immune cells.

PAPER III: In resolved psoriasis, epidermal resident T cells and LCs maintain a pronounced pro-inflammatory profile, whereas dermal T cells are less inflammatory. We observed an enrichment in the expression of the regulatory molecules FOXP3, CTLA4 and PD1 in T cells, and an increased IDO1 expression and IL-10 production by DCs. Clusters of Foxp3+ T cells and DCs were identified in the skin of UVB treated patients, hinting at a possible interaction between regulatory T cells and tolerogenic DCs in the dermis of resolved psoriatic lesions.

PAPER IV: Healthy epidermis and dermis harbour phenotypically distinct subsets of Trm cells. Here we focused on the phenotypic and functional plasticity of skin CD8 Trm cells. Dermal Trm cells, mainly CD69+CD103-CD49a-, upregulated CD103 or both CD103 and CD49a after stimulation with TGF-b, IL-2 and IL-15. TCR engagement increased the proportion of CD103+CD49a+ cells. Conversely, epidermal Trm cells exposed to the same conditions did not change their phenotype, but their functional profile was affected by IL-17 polarising cytokines.

Collectively, these studies highlight the high pro-inflammatory potential of epidermal DCs and T cells during different phases of psoriasis. In contrast, dermal cells acquire tolerogenic features in resolved disease. Moreover, we show that the functionality of Trm cells is affected by their surrounding milieu. These results encourage to take compartmental immune responses into consideration in the design of vaccines and targeted therapies.