Microbe-Dependent Induction of IL-9 by CLA+ T Cells in Psoriasis and Relationship with IL-17A

Abstract

IL-9 is present in psoriatic lesions and is produced by lymphocytes. However, it is not known whether this cytokine is induced by relevant pathogenic triggers of psoriasis, such as Streptococcus pyogenes. Here we addressed the production of IL-9 in response to various pathogens in a psoriatic ex vivo model. Extracts of S. pyogenes and Candida albicans triggered the production of IL-9 and also IL-17A and IFN-γ. This induction was dependent on the interaction between CLA T cells and epidermal cells. Neutralization of IL-9 reduced S. pyogenes-induced IL-17A production by CLA T cells but had no effect on IFN-γ production. Also, IL-9 increased the survival of circulating psoriatic CLA T cells. Co-cultures from patients with guttate or plaque psoriasis with S. pyogenes produced similar amounts of IL-9. High cytokine responses in streptococcal-driven guttate patients paralleled peaks in Psoriasis Area Severity Index and anti-streptolysin O levels. Our results confirm that IL-9 promotes inflammation in psoriasis by up-regulating IL-17A production and support the clinical association of the immune response by streptococcal-sensitized CLA T cells with this cytokine, especially in guttate psoriasis.

CLA+ T Cell Response to Microbes in Psoriasis

“…Our studies have shown that, in CPP patients without clinical evidence of S. pyogenes infection, only CLA + T cells respond to this microbe in comparison to healthy controls. This observation indicates that psoriasis patients present an adaptive immune response to S. pyogenes through IL-17A, IL-17F, IL-9, and IFN-γ production ( 20 , 21 , 24 ) and suggests that S. pyogenes modulates the response of the CLA + T cells that maintain psoriatic lesions, i.e., pyogenes infection has been describe to participate in CPP infection, since higher levels of IgG against S. pyogenes proteins are detected in psoriasis patients in comparison to healthy controls ( 25 ). Some studies have reported the presence of the genera Streptococcus in normal and psoriatic skin ( 26 ) and the isolation of S. pyogenes in the skin of GP patients ( 4 ), probably leading to cutaneous immunization and a CLA + T cell-restricted response in psoriasis.…”

“…IL-9 production is dependent on MHC class I and class II presentation, and it preferentially prolongs CLA + T cell survival. Higher amounts of IL-9 were detected in psoriasis patients than in healthy controls, but no differences were observed between GP and CPP patients ( 24 ). IL-9 has been associated with increased IL-17A production in an animal model of psoriasis ( 23 ).…”

“…Like in the case of S. pyogenes , CLA + T cells, together with autologous epidermal cells, preferentially respond to C. albicans extract by inducing IL-9, IL-17A, and IFN-γ production in psoriasis. This response appears to be restricted to CLA + CD4 + memory T cells since CD4-depleted CLA + memory T cells do not respond to this microorganism in a coculture model with psoriasis cells ( 24 ). These results are in line with the expected immune response to C. albicans in the skin.…”

“…IL-17A and IL-17F are clinically validated mediators of psoriasis. S. pyogenes -driven IL-9 production through CLA + T cells supports IL-17A production in human lymphocytes, since in vitro neutralization of IL-9 reduces IL-17A production by 50% ( 24 ).…”

Specific IgA and CLA+ T-Cell IL-17 Response to Streptococcus pyogenes in Psoriasis

“…Variations in the number and phenotype of circulating CLA þ T cells are closely related to improved clinical outcome of patients with psoriasis (Thorleifsdottir et al, 2012). Our group has established a psoriasis ex vivo model based on the coculture of circulant CLA þ or CLA À T cells and autologous epidermal cells, isolated from skin biopsies from patients with lesional psoriasis, which are then activated by a S. pyogenes extract (SE), leading to specific IL-17 response in CLA þ but not CLA À T-cells cultures (Ferran et al, 2013;Ruiz-Romeu et al, 2018.…”