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. 2014 Apr 1;192(7):3111-20.
doi: 10.4049/jimmunol.1302313. Epub 2014 Mar 7.

Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis

Stanley Cheuk  1 , Maria Wikén, Lennart Blomqvist, Susanne Nylén, Toomas Talme, Mona Ståhle, Liv Eidsmo
Affiliations

Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis

Stanley Cheuk et al. J Immunol. .

Abstract

Psoriasis is a common and chronic inflammatory skin disease in which T cells play a key role. Effective treatment heals the skin without scarring, but typically psoriasis recurs in previously affected areas. A pathogenic memory within the skin has been proposed, but the nature of such site-specific disease memory is unknown. Tissue-resident memory T (TRM) cells have been ascribed a role in immunity after resolved viral skin infections. Because of their localization in the epidermal compartment of the skin, TRM may contribute to tissue pathology during psoriasis. In this study, we investigated whether resolved psoriasis lesions contain TRM cells with the ability to maintain and potentially drive recurrent disease. Three common and effective therapies, narrowband-UVB treatment and long-term biologic treatment systemically inhibiting TNF-α or IL-12/23 signaling were studied. Epidermal T cells were highly activated in psoriasis and a high proportion of CD8 T cells expressed TRM markers. In resolved psoriasis, a population of cutaneous lymphocyte-associated Ag, CCR6, CD103, and IL-23R expressing epidermal CD8 T cells was highly enriched. Epidermal CD8 T cells expressing the TRM marker CD103 responded to ex vivo stimulation with IL-17A production and epidermal CD4 T cells responded with IL-22 production after as long as 6 y of TNF-α inhibition. Our data suggest that epidermal TRM cells are retained in resolved psoriasis and that these cells are capable of producing cytokines with a critical role in psoriasis pathogenesis. We provide a potential mechanism for a site-specific T cell-driven disease memory in psoriasis.

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Figures

FIGURE 1.
FIGURE 1.
CD8 and CD4 T cells infiltrate both epidermis and dermis in psoriasis. (A and B) Confocal microscopy of healthy epidermal sheet (A) and cross-sectional projection of healthy and active psoriasis skin (B). CD3 was pseudocolored in red, Collagen IV in yellow, Langerin in green and nuclei in blue. Representative pictures of three to six donors are shown. (C) Representative FACS plots of epidermal and dermal cell suspensions. (D and E) Number of T cells per mm2 skin surface area (D) and CD4:CD8 ratio (E) of FACS analyzed samples, each dot corresponds to one individual. (F) CD103 and CD49a expression of T cells from healthy or active psoriasis skin, representative FACS contour plots gated on live, CD45+, and CD3+ T cells. Two-tailed Mann–Whitney U test used in (D), two-tailed Wilcoxon matched-pairs signed rank test used in (E). ∗∗∗p < 0.001.
FIGURE 2.
FIGURE 2.
RNA expression profiles reveal highly activated epidermal T cells in lesional psoriasis. Relative gene expression of IL17A, IL22, IFNG (A), GZMA, GZMB, PRF1 (B), CTLA4, FOXP3, and IL10 (C) in epidermal and dermal CD8 or CD4 T cells from active psoriasis lesions (A, n = 9) and healthy skin (C, n = 10). Relative gene expression was calculated against the housekeeping gene β2-microglobulin (B2M) as 2−(CT(_target Gene)-CT(B2M)). Two-tailed Mann–Whitney U test corrected for multiple testing by using the Holm–Bonferroni method. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
FIGURE 3.
FIGURE 3.
CD49a expressing CD8 T cells are retained in epidermis at sites of successfully resolved psoriasis. (A and B) Representative clinical photos of resolved psoriasis. (C and D) Number of epidermal CD8 (C), and CD49a expressing CD8 (D) T cells per mm2 surface area were enumerated by flow cytometry. Two-tailed Mann–Whitney U test in testing between the independent groups and two-tailed Wilcoxon matched-pairs signed rank test used in comparing nonlesional (NL) to their paired resolved (UVB or biologics) samples. Significance levels were corrected for multiple testing by using the Holm–Bonferroni method. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
FIGURE 4.
FIGURE 4.
Gene expression profiles in resolved psoriasis revealed retained IL17 and IL22 expression in epidermal T cells. (A–F) Gene expression in epidermal T cells sorted from healthy (n = 10), biologics treated (n = 10, anti-TNF n = 5, anti–IL-12/23 n = 5), and nb-UVB–treated skin (n = 5). Data presented as the percentage of the median gene expression of the corresponding gene from active lesions (n = 9). Dashed line indicated 100% gene expression in active lesions. Two-tailed Mann–Whitney U test in testing between the corresponding groups against the active psoriasis lesions. Significance levels were corrected for multiple testing by using the Holm–Bonferroni method and shown above the data dots of each group. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
FIGURE 5.
FIGURE 5.
Epidermal Th22 and Tc17 were revealed in resolved lesions after several years of treatment upon ex vivo stimulation. (A and C) Representative contour plots of intracellular IL-22 and IL-17A expression in epidermal CD4 T (A) and CD8 T (C) cells after stimulation with PMA and ionomycin in the presence of brefeldin A. (B and D) Pie charts depicting the median proportion of IL-22+IL-17− (blue), IL-22+IL-17+ (red), and IL-22−IL-17+ (gray) production of epidermal and dermal CD4 T (B) and CD8 T (D) cells. Two-tailed Mann–Whitney U test was used in testing between the corresponding groups against healthy CD4 T or CD8 T cells. Significance levels were corrected for multiple testing by using the Holm–Bonferroni method and shown in the corresponding color. ∗p < 0.05, ∗∗p < 0.01.
FIGURE 6.
FIGURE 6.
IL-17 production is maintained by TRM in resolved psoriasis. (A) Representative contour plots of epidermal CD8 T cells in resolved psoriasis lesions depicting CD103 with IL-17A staining after 5 h Ionomycin/PMA stimulation. (B) The proportion of CD103+ among IL-17A–producing live CD8 T cells, healthy skin (n = 7), biologics treated resolved lesions (n = 6) and active psoriasis (n = 5). (C) Representative contour plots of CLA, CD103, IL-23R, and CCR6 expression in epidermal CD8 T cells in healthy skin, resolved, and active psoriasis. (D and E) Bar graph depicting the proportion of CLA+, CCR6+, IL23R+ (A) and CD103+CCR6+IL23R+ (B) expressing epidermal CD8, where percent CD103+CCR6+IL23R+ was calculated by: percentage of CD103+ among CD8+ T cells × percentage of CCR6+IL23R+ cells among CD103+CD8+ T cells). Mean and SD are depicted. Healthy skin (n = 5) biologics-treated resolved psoriasis (n = 5) and active psoriasis (n = 2). *p = 0.012, **p = 0.0079.
FIGURE 7.
FIGURE 7.
Proposed mechanism of TRM cell–driven recurrent inflammation in psoriasis. The healthy skin is populated by epidermal and dermal CD4 and CD8 T cells. In lesional psoriasis, a massive infiltration of IL-17A– and IL-22–producing CD8 and CD4 T cells occurs in both epidermis and dermis. In resolved lesion, epidermal CD4 T cells retain elevated gene expression of IL22. Upon stimulation, epidermal CD4 T cells respond with IL-22 production and epidermal CD8 T cells with IL-17A production. We propose that IL-17A leads to recruitment of inflammatory T cells from the blood and that IL-22 participates in the keratinocyte activation and development of acantosis leading to recurrent and site-specific psoriasis inflammation.
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