Skin Immunity and Tolerance: Focus on Epidermal Keratinocytes Expressing HLA-G

Abstract

Although the role of epidermal cells in skin regeneration has been extensively documented, their functions in immunity and tolerance mechanisms are largely underestimated. The aim of the present review was to outline the state of knowledge on resident immune cells of hematopoietic origin hosted in the epidermis, and then to focus on the involvement of keratinocytes in the complex skin immune networks acting in homeostasis and regeneration conditions. Based on this knowledge, the mechanisms of immune tolerance are reviewed. In particular, strategies based on immunosuppression mediated by HLA-G are highlighted, as recent advances in this field open up perspectives in epidermis-substitute bioengineering for temporary and permanent skin replacement strategies.

Keywords: HLA-G; human skin; immunity; keratinocytes; resident immune cells; tolerance.

Figure 1

Immune properties of skin keratinocytes. (A) Cellular components of the skin immune system. The skin is a barrier that protects against injury, pathogens, chemicals and radiation. The local immune system includes resident immune cells and cells recruited from the periphery. The epidermis hosts effector cells, such as CD8⁺ T-cells and Langerhans cells that migrate to lymph nodes to perform antigen presentation. In the dermis, Treg cells, NK, CD4⁺ T-cells, mast cells, ILCs, macrophages and dendritic cells participate in immune activities. In addition, resident non-hematopoietic skin cells have immune functions, which are not fully elucidated. (B) Keratinocyte interactions with immune cells. Keratinocytes recognize pathogen-associated molecular patterns (PAMPSs) through TLR and NLR receptors and stimulate the recruitment of resident memory T-cells, dendritic cells and circulating T-cells through pro-inflammatory cytokine secretion. On the other hand, they are also able to promote tissue homeostasis through anti-inflammatory cytokine secretion (IL-34, IL-10). (C) Keratinocytes participate in the regulation of inflammation and the maintenance of skin immune memory. Keratinocytes promote inflammation through IL-1, IL-3 and IL-6 secretion, but also limit it through TSLP and TGFB secretion. Keratinocytes can promote the maintenance of immune memory through various mechanisms, including TGFB, IL-7 and IL-15 secretion.

Figure 2

Candidate immunomodulatory strategies in epidermis. There are two main strategies to reduce keratinocyte immunogenicity for epidermis grafting. The first one is to decrease MHC1, MHC2 and co-stimulatory molecules such as CD40, which limits the ability of keratinocytes to present antigens to T-cells. The second one is to overexpress HLA-G and other immune checkpoint molecules (CD47, PD-L1, CTLA4), to increase tolerance.