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Correspondence: Michael D. Rosenblum, Department of Dermatology, University of California San Francisco, Medical Sciences Building, Health Sciences West - 1201B, 513 Parnassus Avenue, San Francisco, California 94132, USA.
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.
Adhesion is a fundamental process in immune cell function. This is definitively demonstrated by leukocyte adhesion deficiency (LAD) syndrome, a rare genetic disorder caused by defects in a select number of adhesion genes, especially in ITGB2. Without bone marrow transplantation, patients with severe disease are prone to recurrent infections, demonstrate impaired wound healing, and are unlikely to survive beyond 2 years of life (
). Immune responses in peripheral tissues require adhesion pathways to mediate cell recruitment, tissue immunosurveillance, and intercellular interaction between different cell types. These activities are dependent on a large assemblage of adhesion proteins, including integrins, selectins, and cadherins that mediate cell‒cell and cell‒extracellular matrix (ECM) interactions. Contact between adhesion molecules and their ligands provides a means for force transmission and signal transduction that enables cellular movement, positioning, and the tight interactions required for immune synapse formation (
). Adhesive function is directly driven by adhesion proteins but also encompasses the layers of regulatory mechanisms that create cell lineage (i.e., CD4+ T cell vs. CD8+ T cell), cell state (i.e., quiescence vs. activation), and tissue (i.e., skin vs. colon) specificity.
Mammalian skin contains large populations of tissue-resident and recirculating T cells. These cells protect against infection and also play an important role in maintaining skin barrier integrity and tissue homeostasis. Regulatory T cells (Tregs) interact with epithelial stem cells to facilitate differentiation during hair follicle (HF) cycling (
). Performing these functions in the skin requires adhesion-mediated recruitment, interstitial migration, and cell‒cell interaction. In this study, we follow T cells on a journey as they enter and traverse the skin, interact with antigen-presenting cells or malignant cells, and eventually emigrate to draining lymph nodes. We review how the outcome of this journey is determined by the composition of adhesion molecules expressed on various skin T-cell populations and describe how inflammation and immune activation shape adhesive capacity.
Not surprisingly, dysregulation of T cells in the skin is a prominent feature of many skin disorders, and either augmentation or suppression of their activity provides a compelling strategy toward treating human disease (
). Research and clinical efforts in this area have produced several therapies currently approved for the treatment of autoimmune diseases, including multiple sclerosis and Crohn’s disease (
). Unfortunately, these successes have yet to be realized for the treatment of skin disorders. To date, Efalizumab, the only adhesion-targeting therapy approved for a skin disease (psoriasis) was withdrawn from clinical use secondary to severe and potentially life-threatening side effects (
). Nonetheless, rapid progress in understanding the nuances surrounding T-cell adhesion in tissues provides the justification for continued exploration of these pathways as targets for therapeutic manipulation. In this paper, we discuss the attempts to develop therapies modulating T-cell adhesion and examine the opportunities for applying new research findings toward developing treatments for skin disease.
A T cell’s guide to skin adhesion
In the absence of inflammatory signals, tissue-resident T cells, including tissue-resident memory (Trm) cells and dendritic epidermal γδ T cells (DETCs) (in mice), continually survey the skin while other subsets circulate between the tissue, draining lymph nodes, and peripheral blood (
), adhesion molecules are a shared molecular requirement for movement into and through the skin. However, differential induction or activation of adhesion pathways contributes to nuances in the functional behaviors of each population. Broadly, there are four phases of T-cell behavior dependent on adhesion: entry into the skin, interstitial migration, interactions with other cells, and egress from the skin (Figure 1). An individual T cell may not be primed to perform each step sequentially, but it will need to express a specific set of molecules to accomplish any given task. In the following sections, we discuss how T cells use adhesion molecules in the context of each process. However, it should be noted that the majority of research in this field to date has focused on proinflammatory T cells (i.e., conventional CD4+ and CD8+ T cells) and that much less is known about how Tregs utilize adhesion and adhesion-associated molecules to regulate their functions in the skin.
Figure 1Cellular 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.
Cellular adhesion is principally driven by several groups of molecules expressed on T cells, including integrins, selectins, cadherins, and Ig superfamily members (Figure 2) (
). Many additional proteins indirectly influence cellular behavior by regulating the ability of expressed adhesion molecules to bind their ligand. For example, most integrins are present on the cell surface in a relatively closed conformational state with a low affinity for ligand binding. TCR engagement or chemokine exposure produces signaling cascades that induce a conformational change in both integrin subunits. This extends the integrin into an active form and substantially increases ligand affinity (
). Transformation into an active conformation is dependent on the integrin-binding proteins, talin and kindlin, which mediate force transmission through connections to the cytoskeleton (
). Through these cytoskeletal interactions, integrins and other adhesion molecules impart T cells with mechanosensitivity that is essential for navigating the mechanically dynamic tissue environment of the skin (
Figure 2A 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 αEβ7 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.
Interestingly, additional adaptor proteins modulate talin‒integrin interactions leading to cell lineage and cell state‒dependent augmentation of adhesion. Recently, we found that the talin-binding C-type lectin, layilin, is preferentially expressed on highly activated CD8+ T cells infiltrating melanoma tumors but is nearly absent on T cells in peripheral blood (
). CD8+ T cells expressing high levels of IL-17 (Tc17 cells) infiltrating psoriatic lesions are also enriched for layilin expression compared with T cells from healthy skin, suggesting that although layilin may protect against cancer, it could contribute to autoimmunity (
Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer [e-pub ahead of print].
). Differential regulation of integrin activation was also demonstrated between Tregs and CD4+ T-conventional cells. Whereas most CD4+ T cells are entirely dependent on RIAM to mediate β integrin binding to talin, this protein is dispensable in Tregs. Deletion of RIAM protected mice in a spontaneous colitis model owing to a reduced accumulation of effector T cells in the gut, whereas Treg homing to this tissue was normal (
The expression pattern of adhesion molecules themselves also has importance in dictating T-cell function. For T cells to gain access to peripheral tissues, they must express an adhesion signature appropriate for that tissue. Both γδ T cells and αβ T cells require the expression of the glycoprotein CLA to facilitate skin entry by binding to E-selectin expressed on skin endothelial cells (
). Studies examining T-cell recruitment under inflammatory conditions have implicated CD43 and CD44 as additional E-selectin ligands contributing to skin entry (
An analysis of trafficking receptors shows that CD44 and P-selectin glycoprotein ligand-1 collectively control the migration of activated human T-cells.
). Integrin expression is also critical because CD18−/− (the β2 subunit of LFA-1) knockout mice exhibited reduced inflammation in allergic contact dermatitis and delayed-type hypersensitivity reactions owing to impaired T-cell accumulation in skin lesions. Notably, Langerhans cell precursors and dendritic cells (DCs) displayed normal migratory behavior (
). Conversely, mice with a hypomorphic mutation that reduces CD18 levels to 2–16% of wild type spontaneously develop skin lesions mirroring human psoriasis (
). Reduced CD18 was observed to hinder Treg interaction with DCs, impair their suppressive capability, and promote lineage instability by converting Tregs to IL-17‒producing effector T helper (Th)17 cells (
). Another integrin important for skin-specific function (although not for entry into the skin) is αEβ7. CD103 (the αE subunit of αEβ7) is a marker of Trm cells and is widely expressed among T cells in the skin (
). αEβ7 interacts with E-cadherin and likely has a role in positioning T cells within the tissue by allowing an interaction with the epithelium (discussed in detail in the following section) (
). CLA and a related glycoprotein, PSLG-1 (CD162), expressed on T cells bind endothelial E- and P-selectin. In addition, CD44 coassociation with integrin α4β1 (VLA-4) has been found to facilitate early binding to the endothelial ligand VCAM-1 (
). Some nuance has been reported in the mechanisms utilized by different T-cell subsets to initiate tethering. Th1, Th17, and Tregs were found to use a tether and sling behavior to improve adherence efficiency. These subsets were markedly better at forming these structures than Th2 cells, which directly translated into superior attachment to the vessel wall (
). Interestingly, this may explain why tissue-resident Th2 cells are absent in healthy skin of C57BL/6 mice, whereas Tregs and Th1 cells are readily observed (
Low-velocity travel along vessel walls stimulates integrin activation leading to firm adhesion primarily through LFA-1/ICAM-1 and VLA-4/VCAM-1 binding (
). Firm adhesion fully arrests the T cells and allows cytoskeleton reorganization and cellular polarization to form a leading-edge lamellipodium. Lymphocytes then traverse the endothelium primarily through endothelial cell junctions (
Intercellular adhesion molecule-1 enrichment near tricellular endothelial junctions is preferentially associated with leukocyte transmigration and signals for reorganization of these junctions to accommodate leukocyte passage.
). Integrins facilitate transendothelial migration through bidirectional signaling that both increases endothelial permissiveness and directly prepares T cells for tissue entry. LFA-1 engagement with ICAM-1 on endothelial cells induces a MAPK signaling cascade that in turn promotes vascular permeability and induces cytokine and chemokine production (
Intercellular adhesion molecule-1 enrichment near tricellular endothelial junctions is preferentially associated with leukocyte transmigration and signals for reorganization of these junctions to accommodate leukocyte passage.
). In T cells, LFA-1 ligation during transendothelial migration was recently found to drive the synthesis of intracellular complement C3, which was among the most enriched molecular signature of tissue lymphocytes. Examining the T cells from patients with LAD syndrome, the study authors observed reduced C3 mRNA and impaired effector cytokine production (
). Other integrins besides LFA-1 likely contribute to transendothelial migration because the double deletion of the cytoskeletal effector proteins, VASP and EVL, impaired T-cell trafficking into lipopolysaccharide-treated ear skin owing to defective integrin α4 function. Strikingly, T cells deficient in both VASP and EVL exhibited normal crawling and adhesion under shear flow but defective transendothelial migration (
Because T-cell entry into tissue is a critical point in their functional capability, the processes of rolling, firm adhesion, and transendothelial migration are highly influenced by inflammatory and pathologic conditions. Such stimuli modify adhesion molecule expression on both T cells and the endothelium to regulate lymphocyte entry into the skin (
). For example, analysis of peripheral blood from both adult and pediatric patients with atopic dermatitis (AD) revealed the expansion of CLA+ Th2 cells, consistent with the type-2 inflammatory skew of this disease (
Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population.
). In ex vivo transendothelial migration experiments, blood-derived T cells from patients with scleroderma exhibited significantly enhanced migratory ability compared with healthy control cells (
). In support of these findings, CD4+ T cells from patients with scleroderma not only expressed elevated levels of CD11a (the αL subunit of LFA-1) but also reduced the methylation of the CD11a promoter, indicating an epigenetically encoded propensity for increased integrin expression (
). These results suggest that in patients with skin disease, circulating T cells are likely ectopically primed for tissue entry.
Interstitial migration
After passing through the endothelium, T cells enter into a complex 3‒dimensional interstitial space comprising tissue cells, soluble signaling mediators, and the ECM. T cells must integrate cues from this environment to patrol the tissue and position themselves within the skin microarchitecture (
). Cutaneous tissue is a dynamic and high-force environment that experiences differential levels of mechanical stress across the epidermis and dermis and during tissue renewal (
). Notably, injury and inflammation precipitate the remodeling of the ECM, which influence the signals T cells receive through their adhesion receptors (
). Consequently, T-cell motility behaviors (i.e., travel speed and area of immunosurveillance) are directly dictated by the mechanical landscape within the tissue (
). In contrast, CD8+ T cells and DETCs preferentially associate with the epidermal basement membrane (BM), although in healthy human skin, a relatively large proportion of CD8s inhabit the epidermis and are capable of migrating back and forth between the dermis and epidermis (
). Interstitial motility of skin T cells was presumed to be through integrin-independent amoeboid crawling, as has been described in lymph nodes and for myeloid cells (
). Patrolling T cells use the ECM as a scaffold for interstitial migration, relying on αvβ1 and αvβ3 interactions with fibronectin-decorating collagen fibers (
). In this process there is also evidence of subset-driven variation because Th2 differentiation increases αvβ3 expression compared with Th1 cells. Functionally, Th2 cells were observed to patrol a larger area of inflamed dermis than Th1 cells, and manipulation of αvβ3 levels was sufficient to reverse this behavior (
Transit between the dermis and epidermis in healthy skin is likely facilitated by pores in the epithelial BM, although this has not been studied in detail (
). Leukocyte trafficking through such structures is presumably an integrin-independent process owing to their dependency on protrusion-based contractile motility when passing through tight spaces (
). Nonetheless, integrin α1β1 blockade with a mAb against α1 (CD49a) markedly reduced the accumulation of T cells in the epidermis of human psoriatic skin xenografts. Treatment with this antibody also mitigated otherwise spontaneous progression of asymptotic transplants toward pathology, implicating epidermal T cells as mediators of psoriasis (
). However, a more recent study examining α1 knockout in murine T-cell responses to Herpes simplex virus infection found no requirement for this integrin in epidermal localization (
). Instead, α1 supported CD8+ Trm cell persistence in the epidermis, promoted the formation of dendrite protrusions in these cells, and was directly linked to effector function through the induction of IFN-γ (
). Given that the original blocking experiments were performed in the context of transplantation and relied on the skin from patients with psoriasis, it is possible that specific inflammatory signals lead to reorganization of the ECM and precipitate a requirement for α1β1 in dermal to epidermal transit. Integrin αEβ7 is another adhesion molecule implicated in T-cell function at the epithelium. Induced on T cells by TGFβ signaling, αEβ7 binds to E-cadherin, which is highly expressed on epithelial cells (
). Trm cells deficient in CD103 demonstrated increased motility within the epidermis, suggesting that this integrin acts to locally restrain (or guide) T-cell migration (
). Consistent with this possibility, deletion of CD103 did not impact the entry of CD8+ Trm cells in the epidermis but was required for their continued persistence at this skin compartment (
In addition to meditating motility, adhesion molecules are inextricably linked to T-cell activation and differentiation. LFA-1, VLA-4, and αEβ7 are participants in immunological synapse formation and, through engagement with ligands on antigen-presenting or target cells, modulate TCR signaling (
). This contribution to cell‒cell interaction is directly pertinent to CD8+ effector function because either LFA-1 or αEβ7 is required for efficient cytotoxicity toward cancer cells (
). A B16 melanoma cell line engineered to overexpress E-cadherin was more easily eliminated by immune cells, suggesting that the stoichiometry of integrin‒cadherin interactions between T cells and their targets regulates effector activity (
). Skin epithelium may also be able to provide T-costimulatory signals by LFA-1. Primary human keratinocyte cultures pretreated with IFN-γ were able to activate naïve peripheral blood T cells and induce differentiation toward a Th1 and Th17 phenotype (
). Whereas CD2 ligation is necessary for full T-cell activation, LFA-1 binding to ICAM-1 facilitates cell‒cell contact and promotes productive signaling (
). Targeting molecular regulators of LFA-1 activation, including its inhibitor MAP4K4 and layilin, has shown potential as a strategy for the treatment of tumors and viral infection (
). Notably, S1P receptor antagonism was found to halt lymphocyte egress by inhibiting migration across lymphatic endothelium in an LFA-1/ICAM-1– and VLA-4/VCAM-1–dependent manner (
). Presentation of lymphotoxin by Tregs to lymphatic endothelial cells induces VCAM-1 expression and is associated with Treg emigration to the draining lymph node (
). More recent intravital microscopy experiments revealed that T cells actively crawl through the skin afferent lymphatic capillaries before reaching larger collector vessels. This crawling is dependent on LFA-1 and is modulated by inflammation. Contact hypersensitivity increases T-cell velocity through the upregulation of ICAM-1 on lymphatic endothelial cells. Whereas VLA-4 was dispensable for T-cell movement within the lymphatics, its blockade reduced migration from inflamed skin to the draining lymph node, suggesting a contribution for this integrin to initial lymphatic entry (
Although there is increasing evidence pointing to tissue and cellular specificity as a major driver of adhesion dynamics, many of the molecular pathways discussed earlier are broadly conserved across leukocyte lineages. Transformational advances in understanding T-cell function will come through linking cellular behavior to the biochemistry of adhesion molecules dissected in other leukocytes. For example, although we have highlighted several emerging examples of tissue specificity in T-cell migration, there is significantly stronger evidence for this concept in neutrophil tissue recruitment (
). Contributing mechanisms, such as the existence of a β2 integrin bent-open headpiece conformation that impairs neutrophil adhesion as well as the reverse transendothelial migratory capability of these cells, have not been deeply examined in T cells (
). In addition, focused efforts to understand T-cell adhesion in the context of their natural three-dimensional environment will be of the highest yield. Advances in intravital microscopy as well as organoid culture systems provide promise toward illuminating human T-cell behavior in the skin.
Adhesion-based therapeutics in skin disease: promises and challenges
Because T-cell biology is inextricably linked to cellular adhesion, manipulating these pathways in inflammatory disorders, including in skin diseases, has long been recognized as a compelling therapeutic strategy (Figure 3). However, the fundamental importance and complexity of adhesion biology present an enormous challenge. Designing a drug to target molecules such as integrins requires a deep understanding of molecular mechanisms across multiple biological states, tissues, and cell types and against a backdrop of intrinsic regulatory layers. Nonetheless, overcoming these difficulties presents an exceptional opportunity for creating highly efficacious precision medicines.
Figure 3Strategies 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 αL, 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 αEβ7 on skin-resident T cells (
). 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 (
Therapies targeting adhesion pathways are currently approved for the treatment of autoimmune and inflammatory diseases, including multiple sclerosis, Crohn’s disease, and UC (
). Predominantly, these approaches rely on a mAb-based blockade of integrin function, although a small molecule LFA-1 antagonist, lifitegrast, is currently approved for dry eye disease (
), provides an illustrative example for the successful development of tissue-specific adhesion‒based therapeutics. Vedolizumab binds to a conformational epitope unique to the heterodimerization of human α4 and β7 integrins. This allows precise antagonism of α4β7 interactions with MAdCAM-1 on mucosal endothelial cells (
The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
). Clinical studies and nonhuman primate experiments demonstrate that vedolizumab’s molecular specificity translates into targeted immunomodulation. Healthy subjects and animals treated with vedolizumab exhibited significant loss of β7+ leukocytes from the intestinal tract but not from other tissues (
Vedolizumab’s success in achieving a tissue-specific response contrasts with that of natalizumab, another approved anti-α4β7 monoclonal. Binding an α4 epitope, natalizumab, blocks both α4β7 and α4β1 (VLA-1), which is more widely expressed, including on skin-homing T cells (discussed earlier) (
). Unfortunately, this comparatively reduced specificity manifests in the potential for developing progressive multifocal leukoencephalopathy (PML), a life-threatening CNS side effect due to reactivation of the polyoma John Cunningham (JC) virus (
). Although the exact pathogenesis of this complication remains unclear, blockade of α4β1‒VCAM-1 interaction is a likely culprit. JC virus‒reactive T cells are important contributors to viral control and disease prevention, but in contrast to vedolizumab, natalizumab treatment is associated with a reduction in CNS T-cell populations. (
Efalizumab, which was briefly approved for treating psoriasis before being removed from the market owing to incidences of PML (complication risk of 1 in 400 compared with that of 1 in 1,000 for natalizumab), illustrates an additional complexity in developing integrin-based drugs (
). The mechanisms underlying this response are unclear; however, outside-in signaling through LFA-1 is known to influence α4β1, and crosstalk between these integrins is a feature of their molecular function (
). Therefore, α4β1 downregulation may occur through additional biochemical interactions.
Although efalizumab ultimately proved disappointing, its effectiveness at reducing cutaneous inflammation is clear. A phase 3 clinical trial testing efalizumab in the treatment of psoriasis found that the majority of patients experienced at least a 50% reduction in lesion severity and area (
). Several case reports and small trials have also reported success in using efalizumab to treat hypertrophic lupus erythematosus, lichen planus, and AD (
). Follow-up analysis on patients with relapsing psoriasis after cessation of efalizumab observed renewed T-cell and myeloid skin infiltration in skin lesions (
). In addition to reducing skin homing of pathogenic T-cell clones, efalizumab induces T-cell hyporesponsiveness characterized by attenuated T-cell activation and downregulation of costimulatory and TCR complex molecules (
). Together, these findings support the potential for targeting LFA-1‒mediated adhesion in skin disease.
An alternative approach to integrin blockade is to target selectins and their ligands. Modulation of selectin interactions required for T-cell entry into the skin may improve selectivity toward inflamed tissue because the expression of this molecule is highly sensitive to inflammatory stimuli (
). Although methotrexate has broad effects, it is interesting that at least some of its anti-inflammatory properties are due to the regulation of adhesion molecules and prevention of lymphocyte accumulation in the skin. Specifically, methotrexate treatment reduces endothelial expression of E-selectin and VCAM-1 while also downregulating CLA on T cells (
Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin.
). Preclinical experiments attempting to directly target E-selectin with a blocking mAb successfully prevented human Th2-cell infiltration into human skin xenografts (
A potentially attractive therapeutic approach is targeting integrin modulating proteins. This may have the advantage of inhibiting or augmenting adhesion of specific lymphocyte subsets in specific tissues only in inflammatory or malignant contexts. As mentioned previously, the C-type lectin, layilin, modulates LFA-1 activation on CD8+ T cells and is only expressed on a limited number of lymphocyte populations in inflamed or malignant skin (
Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer [e-pub ahead of print].
). Thus, selective modulation of proteins such as layilin may have a beneficial therapeutic effect with fewer adverse reactions than directly targeting integrins or their ligands.
Conclusions and outlook
Adhesion molecules are critical mediators of T-cell accumulation and function in nonlymphoid tissues. These molecules exert functional effects almost continuously as T cells enter and traverse the skin. This breadth of activity means that adhesion mechanisms are highly complex and exhibit multiple layers of regulation and molecular redundancy. Nevertheless, recent research has uncovered several examples of tissue and cell-type specificities, such as between Th1 and Th2 cells or between Tregs and effector T cells. Small variations in how T-cell populations use adhesion molecules to interact with their local environment can result in a large influence on immune response and disease pathology. Because many inflammatory skin disorders have a strong T-cell component, modulating adhesive interactions has long been considered an attractive therapeutic strategy; yet, this approach has most likely not realized its full potential. Despite the current absence of an approved adhesion-targeting therapy for skin diseases, a detailed understanding of relevant molecular pathways has grown significantly since efalizumab was first developed. Developing drugs to target T-cell adhesion presents a formidable challenge in overcoming intrinsic molecular redundancy and functional complexity. The severe off-target complications associated with efalizumab and natalizumab reinforce this difficulty and emphasize a need to comprehensively consider epitope specificity, expression profile, and molecular regulation in designing therapeutics to modulate cellular adhesion. At the same time, doing so opens the possibility for harnessing exquisite biological precision.
This work was primarily supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health (R01AR071944 and DP2-AR068130) to MDR. JMM is supported by the Human Frontier Science Program Long-term Fellowship (LT000183/2018-L). Illustrations were created, in part, with BioRender.com.
Conflict of Interest
MDR is a consultant and cofounder of Treg Bio., a company focused on regulatory T-cell therapeutics. The remaining authors declare no conflict of interest.
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Effector and regulatory T cells roll at high shear stress by inducible tether and sling formation.
An analysis of trafficking receptors shows that CD44 and P-selectin glycoprotein ligand-1 collectively control the migration of activated human T-cells.
Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population.
Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer [e-pub ahead of print].
Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin.
The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
Intercellular adhesion molecule-1 enrichment near tricellular endothelial junctions is preferentially associated with leukocyte transmigration and signals for reorganization of these junctions to accommodate leukocyte passage.
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