CLA ⁺ T cells in cutaneous diseases

ARTICLE

Auteur(s) : Luis F. SANTAMARIA-BABÍ

Almirall Prodesfarma, Research Center, Cardener, 68-74, 08024 Barcelona (Spain)

Article accepted on 18/11/2003

The migration of circulating T lymphocytes to the skin is not a random process. There is an array of molecules that are preferentially expressed by a subpopulation of circulating antigen-experienced T cells that allow them to reach cutaneous sites under normal and inflammatory conditions. Those cells are memory CD45R0⁺ T cells with skin-homing capabilities, and the elements that facilitate their tropism to the skin are different adhesion molecules, enzymes and chemokine receptors that together contribute, as a bar code, to their cutaneous localization. The CLA antigen is considered as a homing receptor for T cells with tropism for the skin. The study and characterization of CLA⁺ T cells in skin diseases is giving new opportunities to study T cell-mediated pathologies from the specific point of view of the cutaneous immune system. The goal of this review is to present some of the most relevant advances in the role of CLA⁺ T cells in skin diseases, highlighting some common features of those cells in different pathological situations.

The CLA antigen on T cells

The CLA antigen is a carbohydrate structure, similar to the sialyl Lewis X antigen, which is expressed on memory (CD45RO⁺) T cells as an epitope of a single cell-surface protein named PSGL-1 [1]. It is expressed by more than 90% of infiltrating T cells present in cutaneous inflammatory sites, but less than 20% of T cells in other non-cutaneous sites [2-5]. The CLA antigen is also present in about 15% of peripheral T cells [2], and is induced on T cells undergoing naive (CD45RA⁺) to memory transition in lymph nodes that drain the skin [6]. The CLA antigen is a ligand for E-selectin, an adhesion molecule that is induced in endothelial cells under inflammatory conditions in response to IL-1 and TNF-α [7]. The interaction of CLA with E-selectin mediates adhesion; this was the initial information that allowed proposing the CLA antigen as a molecule involved in the localization of circulating T cells to the skin [7-8]. It is now known that the extravasation of CLA⁺ to the skin involves several other molecular interactions, as will be described below. Recently, some of the enzymatic mechanisms responsible for the CLA synthesis on T cells have been unraveled. There are several glycosyltransferases which are involved in the generation of sialyl Lewis X, a carbohydrate structure closely related to CLA. Those are core 2 β1,6-N-acetylglucosaminyltransferase-I, N-acetylglucosamine-6-0-sulfotransferase, β1,4-galactosyltransferases, α2,3-sialyltransferase (ST3GaIIV), and α1,3-fucosyltransferases IV and VII (FucTIV and FucTVII) [9]. ST3GaIIV, FucTIV and FucTVII participate in the final synthesis of sialofucosylations of E-selectin ligands expressed by PSGL-1 [10, 1, 11]. From all the glycosyltransferases, FucTVII and FucTIV are the best-characterized enzymes in the process of skin homing. Thus, mice genetically deficient in FucTVII show a substantial contact hypersensitivity deficiency but not a reduced inflammation in other organs [12]. However, mice deficient for both FucTVII and FucTIV manifest a complete abrogation of contact hypersensitivity [13]. These results indicate that FucTVII and FucTIV participate in the synthesis of E, L, and P-selectin ligands, which are relevant in the lymphocyte recruitment to lymph nodes and the skin in the mouse.
The cytokine IL-12 has been identified as a relevant inducer of CLA, since IL-12 induces the synthesis of Fuct VII on T cells undergoing naive to memory transition [14]. In contrast, IL-4 has been shown to inhibit FucTVII expression [14-16]. In vitro, activation of peripheral blood lymphocytes with SEB superantigen has been shown to induce the generation of CLA⁺ T cells, a mechanism that depends on the production of IL-12 [17]. Two different pharmacological approaches that inhibit superantigen-induced activation can reduce CLA induction on T cells. First, the pharmacological inhibition of IL-12 production with phosphodiesterase 4 inhibitors reduces the generation of CLA⁺ T cells induced by SEB [18]. Second, the proteasome inhibitor PS519 reduces the expression of CLA induced by TSS-1 [19]. Interestingly, melanoma patients receiving IL-12 experienced a peripheral burst of CLA⁺ T cells [20]. This observation supports the relevance of IL-12 as a cytokine involved in the induction of CLA expression on T cells.
The inhibition of the CLA synthesis might constitute a way to obtain cutaneous anti-inflammatory activity in vivo. For example, the proteasome inhibitor PS519 that blocks the degradation of the inhibitory protein I kappa B reduced the severity of psoriasis in a SCID-human xenogeneic psoriasis transplantation model [19]. Also, a fluorinated analog of N-acetylglucosamine peracetylated-4-fluorinated-D-glucosamine (4-F-GlcNac), a metabolic inhibitor of CLA synthesis [10], prevents the effector phase of allergic contact dermatitis in mice [21]. This supports the relevance of the CLA antigen as a therapeutic target for T cell-mediated dermatoses.

Migration mechanisms of CLA⁺ T cells from blood to the skin

The CLA antigen participates in the complex molecular interactions between circulating lymphocytes and cutaneous vascular endothelium that takes place during the lymphocyte migration to the skin. The multistep process of leukocyte extravasation [22] can also be applied to the migration of CLA⁺ T cells to the skin [23]. Under inflammatory conditions, proinflammatory mediators like IL-1 and TNF-α upregulate the expression of several adhesion molecules, like E-selectin and ICAM-1, on the surface of endothelial cells. Selectins are responsible for adhesion/tethering and rolling, a process that allows circulating leukocytes to sample the endothelium surface for other molecules like chemokines and adhesion molecules of the immunoglobulin-superfamily like ICAM-1. The interactions between CLA/E-selectin, VLA-4/VCAM-1 and LFA-1/ICAM-1 are required in the transendothelial migration of circulating CLA⁺ T cells [23-25]. In SCID mice grafted with human skin, 14 days after administration of allogenic human T cells, allogenic CLA⁺ T cells were found infiltrating human skin sites suggesting that in an in vivo situation, CLA⁺ T cells have the ability to migrate to human skin [26]. Recently it has been shown that CLA⁺ T cell migration to human skin grafted into SCID mouse can be prevented by an anti-E-selectin antibody. Those results validate the relevance of the CLA/E-selectin interaction in the migration of human T cells to the skin [27]. Chemokines are critically involved in the migration of lymphocytes to tissues [24]. Among other functions, chemokines allow integrin recognition of their counterreceptors present on endothelium by inducing lymphocyte activation and integrin conformational change [28]. They are also involved in the change of morphology of the lymphocyte during diapedesis [28]. Chemokines mediate their effect by their interaction with specific chemokine receptors present on the surface of leukocytes. Several chemokine receptors have been detected on the surface of CLA⁺ T cells that are thought to participate in their migration to skin. These include CXCR2 [29], CCR4 [30], CCR6 [31], CXCR3 [32] and CCR10 [33]. Of all these receptors, CCR10 may be one of the most interesting for several reasons. Unlike the ligands of the chemokine receptors mentioned above, the CCR10 ligand CTACK/CCL27 (cutaneous T cell-attracting chemokine) [34] is mainly produced in the skin by basal keratinocytes, is upregulated in cutaneous inflammation [35], and so far, it has not been found to be expressed in other tissues. Moreover, the expression of CCR10 on T cells is restricted to the CLA⁺CD4⁺ subset [36]. Furthermore, in a mouse model of hapten induced cutaneous inflammation, an anti-CTACK antibody appears to be more potent than tacrolimus in inhibiting the cutaneous reaction [35].

CLA⁺ T cells respond to antigens/allergens preferentially found in the cutaneous microenvironment

Once the participation of the CLA antigen in the multistep process of transendothelial migration of human memory T cells was established [23], it looked feasible that cells that home to the skin could be functionally involved in the immune response of T cell-mediated skin diseases. In principle, a T cell subset with preferential tropism for cutaneous sites should recognize antigens present in the cutaneous microenvironment. In order to address this question, the immunological phenotype of skin-homing T cells was assessed in atopic dermatitis and contact dermatitis [37]. Thus, it was found that in patients with atopic dermatitis the memory T cell response to Dermatophagoides pteronyssinus extract or to the DerP1 allergen was restricted to the circulating CLA⁺ T cell subset. In contrast, in asthmatic patients allergic to Dermatophagoides pteronyssinus, the CLA^– T cell subset preferentially responded. These results indicated that CLA⁺ T cells may not be involved in the immune response taking place in a non-cutaneous inflammatory site such as bronchial mucosa. In fact, no respiratory tract T cell homing receptor has been identified to date [3]. Recently, it has been shown that the CD8⁺ response to a skin-associated viral infection, like for example herpes simplex, is restricted to the CLA⁺ subset, whereas CD8 response to non cutaneous-related viral infection such as EBV or CMV was present in the CLA^– subset [38]. Another relevant feature of CLA⁺ T cells associated to their recirculation capacity between blood and skin was found in freshly isolated CLA⁺ T cells from the blood of patients with active atopic dermatitis. These cells spontaneously produced IL-4 without the need for TCR dependent activation, and expressed increased levels of activation markers such as HLA-DR [37]. These data are in agreement with the fact that lymphocytes coming from the skin and present in draining lymph nodes express high levels of CLA antigen [39], and that allergen-specific T cells have an increased lifespan [40]. In addition, in contact dermatitis to nickel, the proliferative response to the hapten was also clearly restricted to the CLA⁺ T cell subset [37]. These results have been confirmed and completed by other groups. The relevance of these findings opened new research lines in different diseases, and contributed to understanding of the pathological mechanisms of other cutaneous diseases [25], as is commented below.

Function of CLA⁺ T cells in cutaneous skin diseases

Atopic dermatitis and contact dermatitis

The CLA⁺ T cell population is considered to be involved in the initiation of atopic dermatitis lesions [41]. In patch tests elicited by house dust mites, 12 hours after the allergen application, vascular E-selectin, VCAM-1 and ICAM-1 appear in parallel with the infiltration of CLA⁺ T cells [42]. CLA⁺ T cells preferentially recognize house dust mite allergens [37], casein in milk induced eczema [43], and produce Th2 cytokines such as IL-4, IL-5 and IL-13, which prolong eosinophil survival and stimulate IgE production [37, 44]. Moreover, the preferential expansion of CLA⁺ T cells by DerP1 in atopic dermatitis patients allergic to house dust mite has been also assessed at a single cell level [45]. The possible interaction between superantigens derived from Staphylococcus aureus (S. aureus) and CLA⁺ T cells has also been recently studied [46, 47]. In atopic dermatitis patients, a TCR Vβ-skewing for superantigens produced by S. aureus has been found in circulating CLA⁺ T cells, but not for the CLA^– subset. Thus, superantigens present in skin lesions can activate resident skin-homing T cells, and induce the CLA antigen and produce their polyclonal expansion [17]. Another piece of data that supports a relevant role of CLA⁺ T cells in atopic dermatitis comes from the studies of the chemokine receptor CCR4 and its ligands MDC/CCL22 and TARC/CCL17. CLA⁺CCR4⁺ T cells are upregulated in atopic dermatitis and TARC/CCL17 is produced by keratinocytes of atopic dermatitis lesions. Serum levels of TARC/CCL17 have been shown to correlate with atopic dermatitis activity [48]. Recently it has also been shown that serum levels of CTACK/CCL27 correlates with SCORAD [49]. In contact dermatitis, not only circulating CLA⁺ T cells preferentially respond to nickel [37], but also the T cell clones generated from biopsies of contact dermatitis express the CLA antigen on their surface [50, 51]. Moreover, infiltrating T cells in contact dermatitis lesions express CCR10 on their surface [35].

Psoriasis

Psoriasis lesions express TARC/CCL17, MIP-3α/CCL20 and CTACK/CCL27 [30, 31, 35, 25], chemokines that are specific for CCR4, CCR6 and CCR10, respectively. Those chemokine receptors are expressed on CLA⁺ T cells. It has been shown that in the uninvolved skin distant from the plaque edge, before epidermal hyperproliferation takes place, a significant infiltration of CLA⁺ T cells is observed [52], suggesting that those cells might be involved in the initiation of the psoriatic lesion. Psoriasis guttata is the form of psoriasis where the CLA⁺ T cells have been characterized in more detail. Throat streptococcal infection by releasing superantigens and IL-12 may induce memory T cells expressing CLA [17]. Once those cells reach peripheral blood, they migrate specifically to the skin where they are involved in the development of the psoriasis lesions. In fact, the same clonal T cell receptor rearrangement has been found in CLA⁺ T cells present in the tonsils of patients with streptococcal throat infection as in T cells present in skin lesions from the same patients [53]. Some studies have investigated CLA⁺ T cells in chronic plaque psoriasis. Thus, it has been shown that group A streptococcal antigens [54] lead to an increased percentage of bacterial superantigen-related TCR Vβ2 within the subset of circulating CLA⁺ T cells [52]. There is also a correlation between the number of circulating CLA⁺CD8⁺ T cells and the severity of the disease [55]. The potential relevance of targeting CLA⁺ T cells for the treatment of chronic plaque psoriasis comes from recent studies showing that the use of pan-selectin antagonist might be of relevance for psoriasis. Thus, bimosiamose has been shown to clinically improve psoriasis in a recent clinical study [56]. Also, efomycine M is active in a mouse model of psoriasis, where SCID mice are transplanted with lesional psoriatic skin from patients [57]. These studies suggest that blocking the interaction of E-selectin with its ligands may be of clinical benefit in psoriasis. In addition, as has been mentioned before, the proteasome inhibitor PS-519 has been shown to be therapeutically effective in a SCID-human psoriasis transplantation model induced by superantigen activated T cells [19]. Finally, it should be remarked that the mechanism of action of novel biological treatments for psoriasis like alefacept and efalizumab are related to the function of CLA⁺ T cells. Thus, alefacept depletes circulating memory T cells [58] and efalizumab inhibits LFA-1-dependent leukocyte extravasation into skin [59]. Interestingly, CLA⁺ T cells are memory T cells [7] that cross endothelium by LFA-1/CAM-1 interaction [23, 24].

Drug induced delayed type cutaneous allergic reactions

The study of CLA⁺ T cells in drug induced allergic reactions with cutaneous manifestation has allowed an in vivo monitoring of the immune response to those drugs. As in other skin diseases, subjects with allergic drug reactions expressed increased levels of CD3⁺CLA⁺ lymphocytes, and in some cases their activated state paralleled the clinical symptoms [60-62]. After a controlled re-exposure of the patient to the drug, a significant increase in the percentage of CLA⁺ T cells expressing the activation marker HLA-DR is evidenced [63]. Moreover, the memory T cell response to beta-lactams resides in circulating CLA⁺ T cells [64]. Patients with anticonvulsant-induced toxic epidermal necrolysis (TEN) have CLA⁺ T cells present in the skin blisters [65-66]. Interestingly a histopathology study has shown that in TEN lesions CLA⁺ T cells are found at the dermoepithelial junction [65].

Cutaneous T cell lymphoma (CTCL)

The mechanisms of migration of CTCL cells to the skin might also be similar to those used by normal memory T cells in inflammation. Originally it was shown that CTCL patients have an increased percentage of CLA⁺ T cells in circulation, and that those levels correlated with the extent of their cutaneous lesions [67]. Moreover, patients with erythrodermic CTCL manifest a significantly increased percentage of circulating CLA⁺ CD45R0⁺ when compared with patients in remission or with minimal patch-plaque CTCL [68]. More recently, the relevance of the chemokine receptor CCR4 and its ligands TARC and MDC has been highlighted in CLA⁺ T cells in CTCL. CTCL patients with peripheral involvement have a significantly increased percentage of circulating CLA⁺CCR4⁺ [69], as well as cutaneous infiltration of CLA⁺CCR4⁺ cells, and expression of TARC/CCL17 and MDC/CCL22 in the cutaneous lesions. Those studies suggest a critical role of the CLA antigen in the accumulation of lymphoma T cells in the skin.

Other cutaneous diseases

Skin-homing CLA⁺ T cells have been studied in three autoimmune skin diseases: vitiligo, bullous pemphigoid, and alopecia areata. In vitiligo, melanocyte-specific T cell clones express the CLA antigen on their surface [70], and CLA⁺ T cells in the skin of those patients are mainly detected clustered in the vicinity of disappearing melanocytes [71]. In bullous pemphigoid, circulating CLA⁺ T cells express a predominant Th2 phenotype characterized by the production of IL-4 and IL-13 [72]. Interestingly, patients with bullous pemphigoid responding to corticosteroid treatment show a decrease in the number of circulating CLA⁺ Th2 cells and an increase in CLA⁺ T cells producing IL-10 [72]. In the case of alopecia areata, most of the T cells infiltrating around hair follicles are CLA⁺ [73], and the elevated frequency of circulating CLA⁺ CD4⁺ and CLA⁺CD8⁺ decreases in patients with a good clinical course [73]. Finally, in melanoma, tumor infiltrating lymphocytes express the CLA antigen, and immune destruction of melanocytes in halo nevi is associated with the local expansion of T cells expressing the CLA antigen [74-75].

Common features of CLA⁺ T cells in cutaneous diseases

Besides being present in cutaneous lesions of most T cell-mediated skin diseases [2, 25], CLA⁺ T cells share two interesting phenotypical features in different skin diseases (Table I). First, skin-homing CLA⁺ T cells recognize relevant antigens/allergens involved in pathological processes, and second, their frequency or activated state in circulation correlate with the clinical course of disease. These two properties suggest that, under inflammatory conditions, circulating CLA⁺ T cells leave the blood stream to enter the cutaneous environment, where they react with cutaneous antigens, produce cytokines and interact with different elements present in the cutaneous microenvironment. Then, due to their recirculation capacity, they leave the cutaneous inflammatory site and migrate back into the blood where their frequency and activation state manifest their involvement in an immune reaction. Finally, their blood levels tend to normalize once the cutaneous inflammation disappears. Based on all the information presented, the CLA antigen can be viewed as a vehicle that is involved in guiding memory T cells to the skin in different cutaneous diseases. In each pathological scenario, CLA⁺ T cells might present different phenotypical features (e.g. cytokine production and antigen/allergen specificity), related to the specific immune-inflammatory cutaneous process where they participate. n

Acknuwledgements. I thank Dr. Rick Roberts for assistance with the English language.

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