CD8+ T Cells in the Lesional Skin of Atopic Dermatitis and Psoriasis Patients Are an Important Source of IFN-γ, IL-13, IL-17, and IL-22

Hijnen, DirkJan; Knol, Edward F.; Gent, Yoony Y. J.; Giovannone, Barbara; Beijn, Scott J.P.; Kupper, Thomas S.; Bruijnzeel-Koomen, Carla A.F.M.; Clark, Rachael A.

doi:10.1038/jid.2012.456

Cited by 243 publications

(195 citation statements)

References 34 publications

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“…The inflammatory cytokines IL-17, IFN-g, and IL-22 are highly produced by both CD4 and CD8 T cells in active psoriasis lesions (2,18), and histological assessment further demonstrates that other cell types such as neutrophils and mast cells also express IL-17 in active psoriasis (2). Thus, analysis of full skin biopsies will not reveal the different expression profiles of CD4 and CD8 T cells or discriminate between epidermal and dermal T cells.…”

Section: Activated T Cells Preferentially Accumulate In Epidermis In mentioning

confidence: 99%

Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

Cheuk

Wikén

Blomqvist

et al. 2014

The Journal of Immunology

331

330

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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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Section: Activated T Cells Preferentially Accumulate In Epidermis In mentioning

confidence: 99%

Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

Cheuk

Wikén

Blomqvist

et al. 2014

The Journal of Immunology

331

330

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“…In addition to Th17 cells, RORgt expression and IL-17A production have been described in CD8 + Tc17 cells and subsets of gd T cells characterized by IL-17 expression. Interestingly, each of these RORgt + IL-17 + lymphocyte subsets has been shown to home to the skin and is implicated in the pathogenesis of psoriasis (9)(10)(11).…”

Section: D4mentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

132

123

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IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

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“…The role of chemokine (c-c motif) receptor 2 and IL-22 in human AD will require further studies. Both CD4 + T cells, which were induced by Langerhans cells and dermal DC (51), and CD8 + T cells, are the major contributors of IL-22 expression in AD lesions (47,52).…”

Section: Pathogenesis Of Atopic Dermatitismentioning

confidence: 99%

New insights in the pathogenesis of atopic dermatitis

Ong

2013

Pediatr Res

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CD8+ T Cells in the Lesional Skin of Atopic Dermatitis and Psoriasis Patients Are an Important Source of IFN-γ, IL-13, IL-17, and IL-22

Cited by 243 publications

References 34 publications

Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

New insights in the pathogenesis of atopic dermatitis

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