Eavesdropping on the conversation between immune cells and the skin epithelium

Abstract

The skin epithelium covers our body and serves as a vital interface with the external environment. Here, we review the context-specific interactions between immune cells and the epithelium that underlie barrier fitness and function. We highlight the mechanisms by which these two systems engage each other and how immune-epithelial interactions are tuned by microbial and inflammatory stimuli. Epithelial homeostasis relies on a delicate balance of immune surveillance and tolerance, breakdown of which results in disease. In addition to their canonical immune functions, resident and recruited immune cells also supply the epithelium with instructive signals to promote repair. Decoding the dialogue between immunity and the epithelium therefore has great potential for boosting barrier function or mitigating inflammatory epithelial diseases.

Keywords: DETCs; Langerhans cells; epithelial immunity; regeneration and repair; regulatory T cells.

Fig. 1.

Establishment of immunity during epidermal development. Early in embryonic development, the epidermis is specified as a single layer of progenitors that stratify to give rise to the differentiated superbasal layers. The outermost layer of the epidermis is known as the stratum corneum and provides a watertight barrier. LCs and DETCs colonize prior to birth and rely on local survival factors (IL-34 and IL-7/IL-15, respectively) produced by adjacent keratinocytes. Within moments of birth, the skin is colonized by commensal microbes, which inhabit the surface of the skin and invaginations like hair follicles. Commensal colonization induces CCL20-mediated migration of commensal-specific CCR6⁺ Tregs into neonatal skin.

Fig. 2.

Epithelial inflammation and memory. Under homeostatic or ‘naive’ conditions, epithelial cells tether to each other by forming adherens junctions via E-cadherin and p120, which keeps inflammatory NF-κB activation at bay. These adherens junctions in the plasma membranes of the cells at the top-left of the figure (purple arrow heads) are shown in more detail below them. Barrier disruption and loss of cell-to-cell contact result in p120-mediated NF-κB nuclear translocation and in expression of inflammatory cytokines and chemokines. Epithelial cells express a number of PRRs that sense PAMPs and DAMPs including TLRs, NLRP3 and AIM2. Ligation of these receptors also induces downstream inflammatory transcriptional programs and/or activation of the inflammasome and processing of cytokines from the ‘pro’ to active forms. In some instances, ligation of TLRs can also be anti-inflammatory. Following skin injury, LTA from the commensal bacterium S. epidermidis dampens TLR3-mediated inflammation in a TRAF1-dependent manner. Inflammatory cytokines secreted by epithelial cells modulate immune cell function and can also signal autonomously into the epithelium to activate inflammatory transcription factors such as STATs, NF-κB and IRFs. Following resolution, epithelial progenitors retain a memory of inflammation by maintaining chromatin accessibility at key stress-response genes. These ‘poised’ loci enable a more rapid transcriptional response to secondary stimuli.