T cells in the skin: Lymphoma and inflammatory skin disease

Review article T cells in the skin: Lymphoma and inflammatory skin disease Ben Roediger, PhD, a and Christoph Schlapbach, MD, PhD b Bern and Basel, Switzerland T cells are established contributors to the pathogenesis of atopic dermatitis and psoriasis; yet, whether they are the key drivers or simply unwitting participants remains incompletely understood. Conversely, malignant T cells are the undisputed culprits of cutaneous T-cell lymphoma (CTCL), a group of diseases that share key clinical, histopathologic, and molecular features with inflammatory skin disease (ISD). Here, we compare the pathogenesis of ISD and CTCL and discuss the resulting insights. Recurrent, skin-limited disease implicates skin-resident memory T cells in both ISD and CTCL. In CTCL, malignant T cells recruit benign T cells into inflammatory skin lesions, a disease-amplifying function that has also been proposed for pathogenic T cells in ISD. Mechanistically, cytokines produced by malignant T cells in CTCL and by pathogenic T cells in ISD, respectively, are likely both necessary and sufficient to drive skin inflammation and pruritus, which in turn promotes skin barrier dysfunction and dysbiosis. Therapies for ISD target T-cell effector functions but do not address the chronicity of disease, whereas treatments for CTCL target malignant T cells but not primarily the symptoms of the disease. Integrating our understanding of ISD and CTCL can result in important insights into pathogenesis and therapy that may improve the lives of patients in both of these disease groups. (J Allergy Clin Immunol 2022;149:1172-84.) Key words: Atopic dermatitis, cutaneous T cell lymphoma, inflammatory skin disease, malignant T cells, pathogenic T cells Chronic inflammatory skin diseases (ISDs) comprise a wide range of cutaneous disorders that clinically manifest in variable combinations of erythema, plaques, scaling, pruritus, and pain. ISDs are also accompanied by a variety of histopathologic features, including epidermal thickening, spongiosis, parakera- tosis, and (near universally) T-cell infiltration. The 2 most common T-cell–driven ISDs are atopic dermatitis (AD) and psoriasis; for the purposes of this review, the term ISD will refer to AD and psoriasis unless otherwise specified. Cutaneous T-cell lymphoma (CTCL) encompasses a similarly heterogeneous collection of T-cell malignancies of the skin. Arguably, the best understood variants of CTCL are mycosis fungoides (MF) and S ezary syndrome (SS), which have distinct and overlapping phe- notypes that are discussed in this review. ISD and CTCL demon- strate striking epidemiologic, clinical, and molecular parallels, and they respond to similar treatments despite being elicited by distinct causes. Drawing comprehensive parallels between ISDs and CTCL generates important insights into the pathogenesis of both disease groups that may both inform and inspire new thera- peutic approaches. CLINICAL, EPIDEMIOLOGIC, AND GENETIC PARALLELS BETWEEN ISD AND CTCL Clinical parallels ISD and CTCL, in particular MF, share many basic skin morphologies (Fig 1). Both may present as erythematous patches, papules, and plaques, whereas it is only in CTCL that skin tumors may develop. 1-3 Secondary morphologies may be eczematous or papulosquamous in both disease groups. Thus, AD and psoriasis are at the forefront of the clinical differential diagnosis of MF. Er- ythrodermic CTCL, which is caused mostly by SS, may resemble primary or secondary erythroderma, which can also be observed in both AD and psoriasis. 4 Abbreviations used AD: Atopic dermatitis CTCL: Cutaneous T-cell lymphoma DC: Dendritic cell EATL: Enteropathy-associated T-cell lymphoma ISD: Inflammatory skin disease JAK: Janus kinase MAPK: Mitogen-activated protein kinase MF: Mycosis fungoides PUVA: Psoralen plus UV-A SOCS: Suppressor of cytokine signaling SS: S ezary syndrome STAT: Signal transducer and activator of transcription T CM : Central memory T TCR: T-cell receptor T RM : Resident memory T From a Autoimmunity, Transplantation and Inflammation (ATI), Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, and b the Department of Derma- tology, Inselspital, Bern University Hospital, University of Bern. Supported by the Swiss National Science Foundation (grant no. 320030_192479); Bern Center for Precision Medicine, Pilot Project grant; and the Ruth & Arthur Scherbath Foundation, project grant (all to C.S.). Disclosure of potential conflict of interest: B. Roediger is a current employee of and holds company stocks with Novartis Pharma AG. C. Schlapbach has received honoraria as an adviser for AbbVie, LEO Pharma, Eli Lilly and Company, and Novartis and has received research funding from PPM Services/Nogra Pharma. Received for publication February 1, 2022; revised February 23, 2022; accepted for publication February 23, 2022. Available online March 3, 2022. Corresponding author: Christoph Schlapbach, MD, PhD, Inselspital, Bern University Hospital, University of Bern, Switzerland. E-mail: [email protected]. The CrossMark symbol notifies online readers when updates have been made to the article such as errata or minor corrections 0091-6749 Ó 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY li- cense (http://creativecommons.org/licenses/by/4.0/). https://doi.org/10.1016/j.jaci.2022.02.015 1172

T cells in the skin: Lymphoma and inflammatory skin disease

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