T-Cell Adhesion in Healthy and Inflamed Skin

Abstract

The diverse populations of tissue-resident and transitory T cells present in the skin share a common functional need to enter, traverse, and interact with their environment. These processes are largely dependent on the regulated expression of adhesion molecules, such as selectins and integrins, which mediate bidirectional interactions between immune cells and skin stroma. Dysregulation and engagement of adhesion pathways contribute to ectopic T-cell activity in tissues, leading to the initiation and/or exacerbation of chronic inflammation. In this paper, we review how the molecular interactions supported by adhesion pathways contribute to T-cell dynamics and function in the skin. A comprehensive understanding of the molecular mechanisms underpinning T-cell adhesion in inflammatory skin disorders will facilitate the development of novel tissue-specific therapeutic strategies.

Keywords: AD, atopic dermatitis; BM, basement membrane; DC, dendritic cell; DETC, dendritic epidermal γδ T cell; ECM, extracellular matrix; HF, hair follicle; JC, John Cunningham; LAD, leukocyte adhesion deficiency; PML, progressive multifocal leukoencephalopathy; Th, T helper; Treg, regulatory T cell; Trm, tissue-resident memory.

Figure 1

Cellular adhesion is required for T-cell function in the skin. To extend immune protection to peripheral tissues, T cells must actively leave circulation, migrate through interstitial spaces, interact with other cells, and eventually return to circulation by lymphatic vessels. Each of these processes is dependent on adhesive interactions between T cells and other cells or between T cells and the extracellular matrix. Expression patterns of adhesion molecules temporally and spatially regulate T-cell dynamics by selectively assisting specific movements. Only those T cells expressing the correct collection of adhesion receptors will be able to traverse the tissue environment. Inflammation controls T-cell access to the tissue by modulating this adhesion molecule signature.

Figure 2

A diverse set of molecules drive T-cell adhesion. (a) To enter the skin, T cells must interact with blood vessel endothelial cells (a, bottom) before crossing the endothelium into the tissue parenchyma. Initial tethering and/or rolling interactions are mediated by low-affinity binding between the T-cell glycoproteins PSLG-1, CLA (a carbohydrate variant of PSLG-1), and CD44, with E- and P-selectin expressed on the endothelium. Firm adhesion and transendothelial migration require high-affinity ligation of the integrins LFA-1 and VLA-4 with the Ig superfamily members ICAM-1 and VCAM-1. Once in the skin, interactions between T cells and skin epithelium as well as the interaction of T cells with infected or cancerous target cells are also integrin dependent (a, top and left). Integrin α_Eβ₇ binding to E-cadherin is especially important for association with the epithelium. (b) Although the expression of cell adhesion molecules is highly sensitive to the inflammatory milieu, several differences in adhesion activity have been observed across T-cell subsets. Heterogeneity in the levels and timing of adhesion molecule expression will directly influence T-cell behavior in the skin, including tissue entry, immunosurveillance, and local migration patterns. Th, T helper; Treg, regulatory T cell; Trm, tissue-resident memory.

Figure 3

Strategies to target adhesion molecules in disease. Several adhesion molecule inhibitors (both small molecules and mAbs) have been developed to treat inflammatory disorders. To date, efalizumab is the only integrin-blocking therapy to have been approved for use in skin diseases, although it was subsequently withdrawn owing to severe complications. Nonetheless, these drugs illustrate potential opportunities and pitfalls in designing adhesion-based therapeutics. Whereas vedolizumab exhibits exquisite specificity by binding to a conformational epitope unique to the heterodimerization of α₄ and β₇ integrins, natalizumab and efalizumab encountered problems owing to the promiscuity of their integrin targets (α₄ and α_L, respectively). Etrolizumab, a β₇ integrin‒blocking monoclonal in phase III clinical trials for the treatment of IBD may have relevance to skin disease given the importance of α_Eβ₇ on skin-resident T cells (Sandborn et al., 2020). One of methotrexate’s proposed mechanisms is the downregulation of selectin and immunoglobulin superfamily molecules expressed on endothelial cells. However, only limited success has been observed with a monoclonal (PF-00547659) targeting MAdCAM-1 on mucosal endothelium (Sandborn et al., 2018). IBD, inflammatory bowel disease.