Abstract
Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.
Highlights
Barrier organs, such as skin, airway and gut epithelia, represent the first-line defense of the organism
To protect the inside of the body from foreign and potentially harmful substances, the skin exhibits various protective defense mechanisms, such as a mechanical barrier formed through tight junctions between keratinocytes; a chemical barrier that consists of an acidic pH; the production of defensins and other antimicrobial peptides (AMPs), proteases and cytokines; and the expression of pathogen-related receptors (PRRs), such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)like receptors [1,2]
The close interactions of activated T cells were stable and even persisted after the extensive washing steps for sample preparation in scanning electron microscopy (SEM) (Figure 1, lower panel), suggesting the set-up of a synapse between antigen-specific T cells and keratinocytes. These results show that the presented in vitro model of allergic contact dermatitis (ACD) closely resembles the in vivo situation with skin-infiltrating T cells interacting with resident cells
Summary
Barrier organs, such as skin, airway and gut epithelia, represent the first-line defense of the organism. Keratinocytes have the ability to respond to a variety of exogenous and endogenous stimuli and are important, active participants in skin immune responses Besides their major role in the first-line defense and production of AMPs [7], keratinocytes influence other immune cells by secreting T cell-modulating cytokines, such as IL-12 and IL-18 [8,9]; by releasing several chemokines that induce the migration of immune cells into the skin [10]; and expressing surface molecules, such as HLA class I and ICAM-1. Keratinocytes can enhance the T helper (Th) and Th17 polarization of naïve T cells through direct cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1, independent of the presence of DCs [20] Despite these findings, still little is known about the influence of keratinocytes on T cell activity. Direct interactions between keratinocytes and T cells have been characterized mainly by emphasizing T cell effects on keratinocytes and not vice versa
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