Abstract
The interplay between keratinocytes and immune cells, especially T cells, plays an important role in the pathogenesis of chronic inflammatory skin diseases. During psoriasis, keratinocytes attract T cells by releasing chemokines, while skin-infiltrating self-reactive T cells secrete proinflammatory cytokines, e.g., IFNγ and IL-17A, that cause epidermal hyperplasia. Similarly, in chronic graft-versus-host disease, allogenic IFNγ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin. However, whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown. Here, we demonstrate that under proinflammatory conditions, primary human keratinocytes indeed activate naive human T cells. This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1. Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells. In particular, keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2. The latter molecule initiated STAT1 signaling and IFNγ production in T cells. Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease. Consequently, local interference with T cell–keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.
Highlights
The crosstalk between keratinocytes (KCs) and T cells plays a pivotal role during the development of chronic inflammatory skin diseases.[1]
The IFNγ was removed, and the KCs were loaded with a superantigen of Staphylococcus aureus (staphylococcal enterotoxin B (SEB)) that enables polyclonal cross-linking of HLA-DR with the T cell receptor (TCR), mimicking antigen recognition by the TCR.[28,29,30]
S. aureus-derived enterotoxin B (SEB) loading of KCs without further pretreatment led to minor inductions of both activation markers, whereas IFNγ pretreatment strongly enhanced the capacity of SEB-loaded KCs to induce T cell activation
Summary
The crosstalk between keratinocytes (KCs) and T cells plays a pivotal role during the development of chronic inflammatory skin diseases.[1]. Thereby, self-reactive T cells, which are activated in skindraining lymph nodes by antigen-presenting cells (APCs), infiltrate the skin and secrete proinflammatory cytokines, e.g., interleukin (IL)-17 and IFNγ.[4,5] In particular, IL-17 family cytokines induce KC proliferation and inhibit KC differentiation.[6,7] in the early phase of the pathogenic cascade, IL-17 together with IL-22 and IFNγ drives a feedforward loop. In response to these cytokines, KCs secrete chemokines (CCL19, CCL20, CXCL1–3, CXCL9, and CXCL10), leading to the recruitment of neutrophils, IFNγ- or IL-17producing T cells, and mature plasmacytoid or myeloid dendritic cells (DCs).[8,9,10,11] In turn, these highly inflammatory skin-infiltrating DCs cause the activation of autoreactive T cells during the amplification phase, thereby boosting inflammation.[12,13]
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