Exploring Mast Cell-CD8 T Cell Interactions in Inflammatory Skin Diseases

Abstract

The skin is exposed to environmental challenges and contains skin-resident immune cells, including mast cells (MCs) and CD8 T cells that act as sentinels for pathogens and environmental antigens. Human skin MCs and their mediators participate in the maintenance of tissue homeostasis and regulate the recruitment and activity of immune cells involved in the pathogenesis of skin diseases. The cutaneous CD8 T cell compartment is comprised of long-persisting resident memory T cells (T_RM) and migratory or recirculating cells; both populations provide durable site immune surveillance. Several lines of evidence indicate that MC-derived products, such as CCL5 and TNF-α, modulate the migration and function of CD8 T cells. Conversely, activated CD8 T cells induce the upregulation of MC costimulatory molecules. Moreover, the close apposition of MCs and CD8 T cells has been recently identified in the skin of several dermatoses, such as alopecia areata. This review outlines the current knowledge about bidirectional interactions between human MCs and CD8 T cells, analyses the alteration of their communication in the context of three common skin disorders in which these cells have been found altered in number or function-psoriasis, atopic dermatitis, and vitiligo-and discusses the current unanswered questions.

Keywords: CD8 T cells; bidirectional interaction; costimulatory molecule; mast cells; signaling pathway.

Figure 1

Direct cell–cell interactions between mast cells (MCs) and CD8 T cells. The tight apposition of antigen-presenting MC and antigen-recognizing CD8 T cell initiates the formation of an immunological synapse (IS; purple cloud) at the contact interface. IS is a platform with a nano-scale gap/distance formed for cell–cell communication and continent exchange. As the first step of T cell activation, the antigenic peptides bind with MHC-I and are presented to CD8 T cells that recognize them with TCR on the cell surface. Following with MHC-TCR interaction at IS, other molecules required for enhanced T-cell activation and structure modulation are recruited. Costimulatory molecules pairs (such as CD28 and CD80/86, OX40 and OX40L, and 4-1BB and 4-1BBL) provide a second signal for the activation of naïve CD8 T cells. ICAM-1/IFA-1 are adhesion molecular pairs that are important for the formation and strengthening of IS structure. MC, mast cells; IS, immunological synapse.

Figure 2

Indirect MC-CD8 T cell interactions can also occur with the antigen cross-presentation by dendritic cells (DCs). Activated MCs, following IgE–FcεRI crosslinking with antigen, can trigger the formation of an immunological synapse (IS) with immature DCs (IS-1). The IS facilitates the transfer of MC-internalised antigens from MCs to DCs. DCs then process and present the transferred material to CD8 T cells with IS-2 for cell activation. MC, mast cells.

Figure 3

Schematic representation of some of the indirect bidirectional interactions between MCs and CD8 T cells. The communication between MCs and CD8 T cells can be realised by soluble mediators. Chemokine–chemokine ligand interactions can provide instructive signals for CD8 T cells. For example, CCL5-CCR5 and CXCL9/10/11-CXCR3 binding can promote cell migration to Th1-type inflammatory sites, while the latter also plays a role in cell activation and differentiation. TGF-β-TGF-βR signals can promote CD8 T cell residency in skin.