IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells

Abstract

Background: Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear.

Objective: To examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD.

Methods: Skin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry.

Results: In peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity.

Conclusion: Our data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that "T17" and "T22" T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for "T17" T cells and epidermal hyperplasia for "T22" T-cells. Given the clinical correlation with disease severity, further characterization of "T22" T cells is warranted, and may have future therapeutic implications.

Figure 1. The cytokine microenvironment in atopic dermatitis (AD) and psoriasis skin lesions

Quantitative RT-PCR analysis of cytokine mRNA expression normalized to hARP in skin biopsies of lesional AD, psoriasis, and normal skin. Th1/Th17(IFNγ/IL-17) polarization was observed in psoriasis, Th2(IL-13) polarization in AD, with upregulation of IL-22 expression in both diseases. *p<0.05, **p<0.01, ***p<0.005.

Figure 2. Circulating CD3⁺ T-cell profiles are similar in atopic dermatitis (AD) and psoriasis

(A) FACS gating used in the analysis of peripheral blood. (B) Frequencies of circulating cytokine-producing CD4⁺ and CD8⁺ T-cells did not differ between AD and psoriasis. Graphs summarize cytokine-producing CD4⁺ and CD8⁺ T-cell subsets in AD and psoriasis blood. Representative FACS plots are shown.

Figure 3. Atopic dermatitis (AD) and psoriasis lesions have distinct T-cell profiles

(A) Graph of CD4⁺ T-cell subsets in AD and psoriasis lesions showing Th1/Th17(IFNγ/IL-17) polarization in psoriasis, Th2(IL-4) in AD, and similar IL-22⁺CD4⁺ frequencies in both. Representative FACS plots follow. (B) Graph of skin CD8⁺T-cell subsets showing Tc1(IFNγ) polarity in psoriasis and IL-22⁺CD8⁺ polarity in AD. Representative FACS plots follow. *p<0.05, **p<0.01, ***p<0.005.

Figure 4. Unique IL-22-producing CD4⁺ and CD8⁺ subsets are abundant in AD lesions

(A) FACS gating used in the analysis of IL-22-producing T-cells. (B) Majority of IL-22⁺CD4⁺T-cells in AD are not Th1, Th2 or Th17 cells. Psoriasis IL-22 is produced by Th1, Th17 and “Th22” cells. Representative FACS plots shown. (C) Majority of IL-22-producing CD8⁺T-cells in AD are “Tc22” cells.

Figure 5. IL-22⁺CD8⁺ T-cell frequency correlates with disease severity

(A) Immunofluorescence showing abundant CD8⁺T-cells in AD dermis. Bar: 100μm. (B) Linear regression showing positive correlation between IL-22-producing CD8⁺T-cells (“Tc22”) and AD clinical severity (SCORAD) (r=0.78, p<0.05). (C) Linear regression of IL-22-producing CD4⁺T-cells (“Th22”) showing positive trend with disease severity but not statistically significant.

Figure 6. Model of major T-cells and their cytokines in chronic skin lesions of psoriasis vs. atopic dermatitis (AD)

In psoriasis, Th1 cells produce IFNg, Th17 cells produce both IL-17 and IL-22 cytokines, and “Th22” cells produce IL-22 but not IL-17. Upregulated IL-17 axis in psoriasis results in increased production of anti-microbial proteins, neutrophil chemoattractants and CCL20 chemokine, while upregulated IL-22 causes epidermal acanthosis. In AD, the Th2 cytokines IL-4 and IL-13 potentially inhibit Th17 T-cell activity resulting in reduced IL-17 effects. Both “Th22” and “Tc22” T-cells in AD are responsible for significantly increased IL-22 levels. The upregulated IL-22 in chronic AD skin may explain the marked acanthosis that is histologically similar to psoriasis, and the defective terminal differentiation seen in this disease.