Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.

Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-alpha, but not IFN-gamma, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-alpha. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders.

[1]  D. Jarrossay,et al.  Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells , 2009, Nature Immunology.

[2]  H. Spits,et al.  Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells , 2009, Nature Immunology.

[3]  Lisa C. Zaba,et al.  IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. , 2009, The Journal of allergy and clinical immunology.

[4]  C. Akdis,et al.  Differentiation and functional analysis of human T(H)17 cells. , 2009, The Journal of allergy and clinical immunology.

[5]  C. Akdis,et al.  Unique Phenotype of Human Tonsillar and In Vitro-Induced FOXP3+CD8+ T Cells1 , 2009, The Journal of Immunology.

[6]  J. Lennerz,et al.  A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity , 2009, Nature.

[7]  S. Poulsen,et al.  IL-23 and T(H)17-mediated inflammation in human allergic contact dermatitis. , 2009, The Journal of allergy and clinical immunology.

[8]  C. Elson,et al.  Late developmental plasticity in the T helper 17 lineage. , 2009, Immunity.

[9]  C. Akdis,et al.  Regulation of the foxp3 Gene by the Th1 Cytokines: The Role of IL-27-Induced STAT11 , 2009, The Journal of Immunology.

[10]  Thomas D. Wu,et al.  The Serine Protease Marapsin Is Expressed in Stratified Squamous Epithelia and Is Up-regulated in the Hyperproliferative Epidermis of Psoriasis and Regenerating Wounds* , 2009, Journal of Biological Chemistry.

[11]  S. Gangemi,et al.  Increased serum levels of IL‐22 in patients with nickel contact dermatitis , 2009, Contact dermatitis.

[12]  J. Ring,et al.  IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response. , 2009, The Journal of allergy and clinical immunology.

[13]  H. Spits,et al.  Human fetal lymphoid tissue–inducer cells are interleukin 17–producing precursors to RORC+ CD127+ natural killer–like cells , 2009, Nature Immunology.

[14]  H. Ljunggren,et al.  Spotlight on IL-22-producing NK cell receptor–expressing mucosal lymphocytes , 2009, Nature Immunology.

[15]  Shinichiro Sawa,et al.  Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. , 2008, Immunity.

[16]  K. Kabashima,et al.  Possible pathogenic role of Th17 cells for atopic dermatitis. , 2008, The Journal of investigative dermatology.

[17]  M. Fei,et al.  IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia , 2008, Nature Medicine.

[18]  L. Fouser,et al.  IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. , 2008, The Journal of clinical investigation.

[19]  B. Becher,et al.  IL-22 Is Expressed by Th17 Cells in an IL-23-Dependent Fashion, but Not Required for the Development of Autoimmune Encephalomyelitis1 , 2007, The Journal of Immunology.

[20]  F. Morel,et al.  A role for T cell‐derived interleukin 22 in psoriatic skin inflammation , 2007, Clinical and experimental immunology.

[21]  A. Murphy,et al.  Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. , 2007, Immunity.

[22]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[23]  C. Akdis,et al.  TH17 cells in the big picture of immunology. , 2007, The Journal of allergy and clinical immunology.

[24]  David Abraham,et al.  Systemic sclerosis: a prototypic multisystem fibrotic disorder. , 2007, The Journal of clinical investigation.

[25]  L. Fouser,et al.  Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides , 2006, The Journal of experimental medicine.

[26]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[27]  K. Asadullah,et al.  IL‐22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis , 2006, European journal of immunology.

[28]  O. Arican,et al.  Serum Levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in Patients With Active Psoriasis and Correlation With Disease Severity , 2005, Mediators of inflammation.

[29]  A. Takayanagi,et al.  Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. , 2005, Gastroenterology.

[30]  H. Volk,et al.  The expression of legumain, an asparaginyl endopeptidase that controls antigen processing, is reduced in endotoxin-tolerant monocytes , 2005, Genes and Immunity.

[31]  B. Kwon,et al.  Human CC chemokine CCL23, a ligand for CCR1, induces endothelial cell migration and promotes angiogenesis. , 2005, Cytokine.

[32]  A. Gurney,et al.  IL-22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human Keratinocytes1 , 2005, The Journal of Immunology.

[33]  M. Falchi,et al.  Immunohistochemical analysis of keratinocyte growth factor and fibroblast growth factor 10 expression in psoriasis , 2005, Experimental dermatology.

[34]  K. Asadullah,et al.  Is there an interaction between interleukin-10 and interleukin-22? , 2005, Genes and Immunity.

[35]  A. Facchini,et al.  IL-17, IL-1β and TNF-α stimulate VEGF production by dedifferentiated chondrocytes , 2004 .

[36]  K. Asadullah,et al.  IL-22 increases the innate immunity of tissues. , 2004, Immunity.

[37]  H. Kleinman,et al.  Angiogenic activity of human CC chemokine CCL15 in vitro and in vivo , 2004, FEBS letters.

[38]  B. Gao,et al.  Hydrodynamic Gene Delivery of Interleukin-22 Protects the Mouse Liver from Concanavalin A-, Carbon Tetrachloride-, and Fas Ligand-induced Injury via Activation of Stat3 Interleukin-22 (il-22) Is a Recently Identified T Cell-derived Cytokine Whose Biological Significance Remains Obscure. Previously, , 2022 .

[39]  K. Unsicker,et al.  Functions of Fibroblast Growth Factor (FGF)-2 and FGF-5 in Astroglial Differentiation and Blood-Brain Barrier Permeability: Evidence from Mouse Mutants , 2003, The Journal of Neuroscience.

[40]  J. Foley,et al.  Hair-cycle-dependent expression of parathyroid hormone-related protein and its type I receptor: evidence for regulation at the anagen to catagen transition. , 2003, The Journal of investigative dermatology.

[41]  Diane Lejeune,et al.  Interleukin-22 (IL-22) Activates the JAK/STAT, ERK, JNK, and p38 MAP Kinase Pathways in a Rat Hepatoma Cell Line , 2002, The Journal of Biological Chemistry.

[42]  T. Imamura,et al.  Fibroblast growth factor 5 inhibits hair growth by blocking dermal papilla cell activation. , 2002, Biochemical and biophysical research communications.

[43]  C. Albanesi,et al.  Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. , 2000, The Journal of investigative dermatology.

[44]  C. Albanesi,et al.  Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. , 2000, The Journal of investigative dermatology.

[45]  U. Pendurthi,et al.  Mechanism for diminished tissue factor expression by endothelial cells cultured with heparin binding growth factor-1 and heparin , 1991 .

[46]  K. Arndt,et al.  Cyclosporine inhibits basic fibroblast growth factor-driven proliferation of human endothelial cells and keratinocytes. , 1989, Archives of dermatology.

[47]  J. Winkles,et al.  Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor). , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[48]  P. Frosch,et al.  Contact dermatitis , 1987, Contact dermatitis.

[49]  G. Rajka,et al.  Diagnostic Features of Atopic Dermatitis , 1980, Acta Dermato-Venereologica.