Lymphotoxin Beta Receptor, but Not Its Lymphotoxin Alpha-Containing Ligands, Is Essential for the Development of Experimental Dermatitis

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Ekaterina A. Gorshkova^1,2,3,a*, Marina S. Drutskaya^1,2,4, Sergei A. Nedospasov^1,2,3,4, and Ekaterina O. Gubernatorova^1,2,3,b*

¹Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

²Center for Precision Genetic Technologies for Medicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

³Department of Molecular Immunology, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

⁴Division of Immunobiology and Biomedicine, Sirius University of Science and Technology, 354349 Sirius Federal Territory, Krasnodar Region, Russia

^* To whom correspondence should be addressed.

Received: January 15, 2026; Revised: April 7, 2026; Accepted: April 7, 2026

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Allergic contact dermatitis (ACD) is a chronic inflammatory skin disorder the development of which is driven by allergen sensitization in peripheral lymphoid organs and local cutaneous inflammation. Lymphotoxin (LT) and its receptor LTβR are critical for lymphoid organogenesis and immune regulation in barrier tissues, but their role in ACD pathogenesis remains incompletely defined. This study aimed to delineate differential contribution of the LTβR-dependent signaling in oxazolone-induced dermatitis. We examined Lta knockout (Lta KO) mice, which lack both soluble LTα3 and membrane-bound isoforms LTα1β2/LTα2β1, and the Ltbr knockout (Ltbr KO) mice, both of which lack lymph nodes. ACD was induced by repeated oxazolone application to ear skin, with assessment of clinical severity, inflammation-associated gene expression, serum IgE levels, and immune cell composition in blood and spleen. Contrary to previous reports, the Lta KO mice developed dermatitis comparable to the wild-type (WT) mice, with elevated IgE production. In contrast, the Ltbr KO mice were substantially protected from the disease, exhibiting attenuated clinical inflammation, reduced ear swelling, and decreased Tslp expression in the lesional skin at the background of a lower proportion of circulating CD4⁺ T cells. These findings indicate that LTβR-dependent signaling is pathogenic in allergic skin inflammation, while LTα-mediated pathways are dispensable, suggesting a potential role for the other LTβR ligand, LIGHT, in ACD pathogenesis. Notably, ACD developed even in the absence of lymph nodes, highlighting the importance of local, skin-resident LTβR-dependent mechanisms in the disease development.

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KEY WORDS: lymphotoxin, thymic stromal lymphopoietin, reverse genetics, oxazolone, dermatitis

DOI: 10.1134/S0006297926600080

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