The role of CLA+T lymphocytes in the development of Atopic Dermatitis

[eng] Atopic dermatitis is the most common chronic immune-mediated inflammatory skin disease affecting up to 20% of children and 10% of adults. The complex pathophysiology of the disease comprises genetic susceptibility, epidermal barrier dysfunction, cutaneous dysbiosis with abundance of S. aureus, an abnormal cutaneous immune system activation with a core Th2 response and pruritus. Cutaneous Lymphocyte-associated Antigen (CLA)+ T cells represent the subset of memory T cells that belong to the cutaneous immune system. CLA+ T cells recirculate between blood and skin through the thoracic duct, specifically respond to skin-related antigens, and represent over 90% of T cells infiltrating the skin. Therefore, CLA+ T cells constitute peripheral cellular biomarkers and, because they can be found in general circulation, they are a source of translational information on the immunological mechanisms taking place in the skin during disease. We have studied atopic dermatitis in the context of the cutaneous immune response through the effector function of CLA+ T cells. For this, we have stablished a novel ex vivo model of adult non- treated moderate-to-severe atopic dermatitis based on circulating CLA+ T cells cocultured with a suspension of autologous epidermal cells obtained from lesional biopsies in the same patients. Then, we have studied the T-cell effector function in response to relevant disease triggers such as S. aureus microorganism and house dust mite (HDM) allergen, as well as the association between cytokine response to the stimuli and patient’s clinical data. First, the study of IL-13 response to S. aureus enterotoxin B (SEB) by CLA+ T cells defined two groups of patients, Th2 high and Th2 low, within a clinically homogeneous population. In the Th2 high group, in contrast to the Th2 low group, the IL-13 response positively correlated with severity, in terms of EASI score, and levels of CCL17, sIL-2R and S. aureus-specific IgE in plasma. Additionally, in this group the IL-13 response directly correlated with CCL26 and indirectly correlated with LCN2 mRNA expression in cutaneous lesions. Conversely, in the Th2 low group, the CLA+ T-cell response to SEB skewed towards Th17, Th22 and Th1. Next, the role of the neuroimmune cytokine IL-31 was examined in our model by studying the CLA+ T-cell response to HDM, and a bimodal (present or absent) IL-31 response in relation with the HDM-specific IgE levels in plasma was observed. Patients producing IL-31 by HDM-activated CLA+ T cells showed increased HDM-specific and total IgE levels and reported an increased inflammatory profile compared to patients with no IL-31 response. Interestingly, the IL-31 response directly correlated with patient’s pruritus intensity and plasma levels of CCL27 and periostin. Of note, patients with no IL-31 response reported raised presence of HDM- specific and total IgE levels compared to control subjects, suggesting that the degree of IgE sensitization to HDM in this group was not enough for inducing IL-31 response. In summary, this novel ex vivo model of adult non-treated moderate-to-severe atopic dermatitis has allowed to functionally identify Th2 high and Th2 low responders from a clinically homogeneous population based on the SEB-CLA+-IL-13 axis, as well as stratifying patients into IL-31 producers and non-producers in relation with the degree of IgE sensitization to HDM by analyzing the CLA+ T-cell response to HDM and its association with clinical features. Altogether, this translational work expands the understanding of the heterogeneous inflammatory response of the disease and may contribute to improving the effectiveness of targeted therapies

SEB-induced IL-13 production in CLA+ memory T cells defines Th2 high and Th2 low responders in atopic dermatitis

Atopic dermatitis; Cutaneous lymphocyte antigen; Skin infectionsDermatitis atópica; Antígeno cutáneo de linfocitos; Infecciones de la pielDermatitis atòpica; Antigen limfòcit cutani; Infeccions de la pellStaphylococcus aureus, memory skin-homing cutaneous lymphocyte-associated antigen (CLA)+ T cells and IL-13 constitute relevant play-ers in atopic dermatitis (AD) pathogenesis.1 Since circulating CLA+ T cells reflect cutaneous abnormalities present in human inflammatory skin diseases,2 an ex vivo coculture model made of purified circu-lating CLA+/− effector and central memory T cells and autologous lesional epidermal cells was established. We show a CLA-dependent production of IL-13 upon activation with staphylococcal enterotoxin B (SEB) that allows the differentiation of the Th2 high and Th2 low groups, with distinct clinical correlations between both groups, within a clinically homogeneous population of adult non-treated moderate-to- severe AD patients

Allergen sensitization stratifies IL-31 production by memory T cells in atopic dermatitis patients

Atopic dermatitis; Memory T cells; PruritusDermatitis atòpica; Cèl·lules T de memòria; PruritDermatitis atópica; Células T de memoria; PruritoBackground: The role of allergen sensitization in IL-31 production by T cells and specifically in the clinical context of atopic dermatitis (AD) has not been characterized. Methods: The response to house dust mite (HDM) in purified memory T cells cocultured with epidermal cells from AD patients (n=58) and control subjects (n=11) was evaluated. AD-associated cytokines from culture supernatants, plasma proteins and mRNA expression from cutaneous lesions were assessed and related with the clinical features of the patients. Results: HDM-induced IL-31 production by memory T cells defined two subsets of AD patients according to the presence or absence of IL-31 response. Patients in the IL-31 producing group showed a more inflammatory profile, and increased HDM-specific (sp) and total IgE levels compared to the IL-31 non-producing group. A correlation between IL-31 production and patient's pruritus intensity, plasma CCL27 and periostin was detected. When the same patients were analyzed based on sp IgE and total IgE levels, an increased IL-31 in vitro response, as well as type 2 markers in plasma and cutaneous lesions, was found in patients with sp IgE levels > 100 kUA/L and total IgE levels > 1000 kU/L. The IL-31 response by memory T cells was restricted to the cutaneous lymphocyte-associated antigen (CLA)+ T-cell subset. Conclusion: IgE sensitization to HDM allows stratifying IL-31 production by memory T cells in AD patients and relating it to particular clinical phenotypes of the disease

Human CLA+ memory T cell and cytokines in psoriasis

Psoriasis is a common inflammatory skin condition resulting from the interplay between epidermal keratinocytes and immunological cellular components. This sustained inflammation is essentially driven by pro-inflammatory cytokines with the IL-23/IL-17 axis playing a critical central role, as proved by the clinical efficacy of their blockade in patients. Among all the CD45R0+ memory T cell subsets, those with special tropism for cutaneous tissues are identified by the expression of the Cutaneous Lymphocyte-associated Antigen (CLA) carbohydrate on their surface, that is induced during T cell maturation particularly in the skin-draining lymph nodes. Because of their ability to recirculate between the skin and blood, circulating CLA+ memory T cells reflect the immune abnormalities found in different human cutaneous conditions, such as psoriasis. Based on this premise, studying the effect of different environmental microbial triggers and psoriatic lesional cytokines on CLA+ memory T cells, in the presence of autologous epidermal cells from patients, revealed important IL-17 cytokines responses that are likely to enhance the pro-inflammatory loop underlying the development of psoriatic lesions. The goal of this mini-review is to present latest data regarding cytokines implicated in plaque and guttate psoriasis immunopathogenesis from the prism of CLA+ memory T cells, that are specifically related to the cutaneous immune system

CLA+ memory T cells in atopic dermatitis

Circulating skin‐homing cutaneous lymphocyte‐associated antigen (CLA)$^{+}$ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL‐13, IL‐31, pruritus, CCL17 and early effects on dupilumab‐treated patients have in common that they are associated with the CLA$^{+}$ T cell mechanisms in atopic dermatitis patients. The function of CLA$^{+}$ T cells corresponds with the role of T cells belonging to the skin‐associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology

Allergen sensitization stratifies IL-31 production by memory T cells in atopic dermatitis patients

Background:The role of allergen sensitization in IL-31 production by T cells and specifically in the clinical context of atopic dermatitis (AD) has not been characterized. MethodsThe response to house dust mite (HDM) in purified memory T cells cocultured with epidermal cells from AD patients (n=58) and control subjects (n=11) was evaluated. AD-associated cytokines from culture supernatants, plasma proteins and mRNA expression from cutaneous lesions were assessed and related with the clinical features of the patients. ResultsHDM-induced IL-31 production by memory T cells defined two subsets of AD patients according to the presence or absence of IL-31 response. Patients in the IL-31 producing group showed a more inflammatory profile, and increased HDM-specific (sp) and total IgE levels compared to the IL-31 non-producing group. A correlation between IL-31 production and patient's pruritus intensity, plasma CCL27 and periostin was detected. When the same patients were analyzed based on sp IgE and total IgE levels, an increased IL-31 in vitro response, as well as type 2 markers in plasma and cutaneous lesions, was found in patients with sp IgE levels > 100 kUA/L and total IgE levels > 1000 kU/L. The IL-31 response by memory T cells was restricted to the cutaneous lymphocyte-associated antigen (CLA)(+) T-cell subset. ConclusionIgE sensitization to HDM allows stratifying IL-31 production by memory T cells in AD patients and relating it to particular clinical phenotypes of the disease