In this report we explored the phenotype and cytokine production of different T-cell subsets in patients with chronic AD as compared to psoriasis. Our findings expand current knowledge on the presence of Th17 T-cells and shed new light on a unique subset of IL-22 producing T-cells in blood () and skin ( and ) compartments of chronic AD patients.
We found a significantly decreased frequency of CD4+
Th17 T-cells in AD lesional skin compared to psoriasis, whereas comparable numbers of these cells were obtained in peripheral blood. However, no significant difference was observed in IL-17 producing CD8+
T-cells (Tc17) in skin lesions of AD and psoriasis. We previously reported that, compared to psoriasis, there was little expression of IL-17 and IL-23 mRNAs in AD lesions.13
In the present study, we found a 2-fold difference in Th17 T-cell frequencies between AD and psoriatic skin lesions and a 20-fold difference in IL-17 mRNA expression. The discrepancy between IL-17/IL-23 mRNA production and Th17 T-cell frequencies could potentially mean that although Th17 T-cells exist in AD lesions, in contrast to psoriasis, they are not activated. Another possibility is that increased Th2 cytokines in AD may directly inhibit IL-17 production.14-16
Evidence has been recently provided for an inhibiting effect of IL-4/IL-13 Th2 cytokines on IL-17-induced antimicrobial protein secretion.17
Ultimately, several factors might collectively contribute to the reduction of Th17/IL-17 in AD skin: 1) Reduced recruitment of Th17 T-cells to AD skin due to either a lack of Th17 attracting chemokines (e.g. CCL20 that is expressed at lower levels in AD skin), or a lack of Th17-polarizing DC;18
2) Failure to activate existing Th17 T-cells, resulting in markedly decreased production of IL-17; and, 3) Active suppression of IL-17 production by antagonistic cytokines.5, 14
Increasing evidence suggests that IL-17 is a master regulator of antimicrobial proteins (AMPs) in keratinocytes, playing a central role in host defense against microorganisms at the surface barrier.17, 19
Decreased IL-17 expression in chronic AD skin has been correlated to reduced expression of key AMPs, potentially accounting for the propensity to skin infections in this disease.13, 17
Nevertheless, the attenuated IL-17/AMP axis in chronic AD lesions does not explain the retained epidermal hyperplasia in this disease that bears histological resemblance to psoriasis.18, 19
A possible explanation for the hyperproliferative and acanthotic epidermis, as well as for disturbed terminal differentiation in AD, might be provided by IL-22. Surprisingly, despite the low frequency of Th17 T-cells, a significantly increased expression of IL-22 mRNA and up-regulated production of IL-22 from CD4+
T-cells was observed in lesional AD skin, as compared to psoriasis. Although IL-22 has some ability to induce antimicrobial peptides like S100A7, it has much stronger effects in regulating hyperplasia and differentiation in keratinocytes.3, 5-7
In reconstructed epidermis, IL-22 induces marked acanthosis, hypogranulosis and suppression of terminal differentiation.8 In vivo
over-expression of IL-22 induces marked hyperplasia and inflammation in murine skin, bearing similarities to both psoriatic and AD skin.9
Moreover, this cytokine down-modulates and inhibits genes involved in terminal differentiation of keratinocytes.3, 7
Among these IL-22-regulated genes are several proteins recently implicated in the epidermal barrier defect in AD, including filaggrin, loricrin, and involucrin.20-25
Our data show that the majority of IL-22 producing T-cells do not co-synthesize IFNγ, IL-4, or IL-17. While the CD4+IL-22+ population is evident in both diseases, a significant proportion of IL-22 production is still derived from Th17 T-cells in psoriasis. In AD, a very large population of both CD4+ and CD8+ cells that uniquely synthesize IL-22 was appreciated, accounting for approximately 70% of the IL-22 production, with low frequencies of Th1, Th2, and Th17 T-cells that co-produce IL-22.
Although IL-22 production was mostly described in IL-17 producing T-cells, a distinct IL-22 producing T-cell population has been previously detected in both mice5
and humans.3, 17
Our data establishes 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 AMPs and pro-inflammatory chemokines by “T17” T-cells, and keratinocyte proliferation and modulation of terminal differentiation by “T22” T-cells (). However, given the inhibitory effect of IL-4 on IL-17 production5, 14
and on IL-17-induced AMPs17
, independent regulation of IL-17 and IL-22 production within a single T-cell population cannot be entirely excluded. Therefore, future experiments must determine whether unique IL-17 and IL-22 producing memory T-cell populations differentiate from naïve T-cells, as opposed to the independent functional modulation of these cytokines within a common T-cell population.
Model of major T-cells and their cytokines in chronic skin lesions of psoriasis vs. atopic dermatitis (AD)
Of particular interest is the CD8+
T-cell population that although highly increased in AD skin, it was negligible in psoriasis, precluding further analysis. Interestingly, we found a strong correlation between the frequency of CD8+
/”Tc22” T-cells, and the AD disease severity index (). This important observation expands a recently reported correlation between lesional CD8+
T-cell frequencies with AD disease severity.26
A critical role for CD8+
T cells in AD was recently indicated in a mouse model that showed that these were the predominant cells responsible for development of AD skin pathology and inflammation.27
In summary, our findings suggest that novel subsets of “Th22” and “Tc22” T-cells contribute to the increased IL-22 expression in chronic AD skin (). Our results support a Th2/T22 immune polarization in chronic AD, compared to the deviation toward a Th1/Th17 phenotype in psoriasis (). The increased IL-22/”T22” signal despite a relative deficiency of Th17/IL-23 pathway in AD, suggests an immune-driven hyperplasia by IL-22, independent of IL-17. Further support to this hypothesis stems from the small frequency of IL-22+ Th17 cells in AD.
Further elucidation of the role of these novel “T22” T-cells in both chronic and acute AD, as well as the interplay between these cells and the Th17/IL-23 pathway to produce the AD phenotype, are warranted. Our data, supported by the clinical correlation with disease severity potentially suggest targeting “T22” T-cells in AD as a promising future therapeutic, that may reverse both epidermal hyperplasia and the disturbed terminal differentiation pattern in this disease. Given the number of emerging biological therapies that directly target IL-22 or the Th17/IL-23 pathway, these investigations become even more critical.