The Role of OX40L/OX40R in Atopic Dermatitis (AD)

The inflammatory prequel is a foundational driver of immune imbalance, where antigen-presenting cell (APC)-driven OX40 ligand (OX40L) signaling leads to dysregulated T-cell activity, heterogeneity, and chronicity. It is characterized by the activation, differentiation, and survival of T cells.^3,4

OX40L binds to the co-stimulatory T cell receptor OX40R, which are both members of the tumor necrosis factor (TNF)/TNF receptor superfamily and function as immune checkpoint modulators that regulate T-cell responses.³ The OX40L signalling pathway plays a key role in controlling the extent of T-cell responses after antigen recognition and T-cell activation, regulating proliferation, expansion and survival of T effector cells, and cytokine release. ⁵ Inflammation in AD is driven in part by activated T cells.⁵

In AD, the OX40L signalling pathway is upregulated, with lesional skin showing a higher increase in OX40R+ T cells and a higher density of OX40L+ dendritic cells compared to healthy or psoriatic skin.^2,6 The OX40L axis acts as a central driver of inflammation in AD by facilitating the interaction between skin-homing memory T cells, ligand-bearing cells such as mast cells within the dermis, and immune cells including regulatory T cells, effector T cells, as well as cytokines.^6,7

What is the OX40L/OX40R Pathway in Atopic Dermatitis and Why Does it Matter? 

OX40L signalling drives effector T cell responses in AD. The OX40L signaling pathway promotes the proliferation, survival, and inflammatory activity of multiple T-effector subsets involved in AD.^3,5

These T-effector cell subsets include Th2 as well as Th1, Th17, and Th22 cells, which help facilitate the progression of acute to chronic AD by promoting keratinocyte proliferation, epidermal thickening, and the production of T cell-recruiting mediators into the skin.³

Activated effector T cells release a broad array of proinflammatory cytokines. These cytokines are key drivers of AD pathophysiology, contributing to skin barrier impairment, amplifying the skin barrier response and promoting fibrosis due to collagen production.⁵ In addition to supporting effector responses, OX40L signaling interaction facilitates the survival and transition of memory T cells.³

OX40R is predominantly expressed on T cells following their activation and its signalling plays an important role in effector and memory T-cell expansion, differentiation and survival through ligation with OX40L, which is expressed on APCs such as B cells and dendritic cells, as well as other cells such as ILC2s and mast cells.^2,8 

Learn more about the immune pathways driving T cell inflammation in AD.

Role of OX40L Signalling in Atopic Dermatitis

OX40L signaling amplifies a central inflammatory pathway in AD by mediating key immune activation signals that drive T-cell activation and dysregulation.^3,8 

OX40R is a costimulatory receptor that is upregulated on activated effector and effector-memory T cells. OX40L/OX40R interactions promote expansion and survival of these T cells.⁶ OX40R is transiently expressed on activated CD4+ and CD8+ T cells following antigen stimulation and its expression is enhanced by proinflammatory cytokines such as IL-2, IL-4, and TNF-α.³

One source of AD pathogenesis is driven by immune system imbalance originating from the inflammatory prequel, where APCs express OX40 ligand, a key inflammatory signal. OX40 ligand binds to the OX40 receptor on T cells, driving sustained T cell proliferation, survival, and cytokine release. This reduces the regulatory and suppressive function of regulatory T cells, allowing the inflammation to progress unchecked, underlining the chronic immune imbalance seen in AD. Excessive overactivation by APCs leads to prolonged and unrestrained inflammation, contributing to chronic disease states and perpetuating disease progression.^2,3,9,10 

The interaction of OX40R with OX40L delivers a costimulatory signal that promotes effector T-cell expansion, cytokine production, and memory T-cell formation, while excessive activation by APCs leads to prolonged, unrestrained inflammation that perpetuates disease progression.³

Role of Memory T cells in Atopic Dermatitis 

Beyond its role in effector T-cell expansion, OX40L signaling mediates the transition of some effector T cells into resting memory T cells.³

Re-exposure to the same antigen drives resting memory T cells to differentiate into effector memory T cells that rapidly express OX40R.³ OX40L binding allows for the expansion of effector T cells, stimulating the production of new proinflammatory cytokines.³

OX40R-expressing effector memory T cells are increased in AD lesions, potentially explaining the immunologic basis for disease recurrence.³ These findings show that OX40R may contribute to the chronicity of AD by maintaining a durable memory T cell population.³

Explore the role of T cells in atopic dermatitis.

Evidence of OX40L/OX40R involvement in Atopic Dermatitis

Elevated expression of OX40L on dendritic cells has been observed in lesional skin from patients with AD, with higher numbers of OX40L⁺ dendritic cells compared to non-lesional, healthy, or psoriatic skin.^2,6 In the dermis, OX40R+ cells co-localize with OX40L+ cells, including mast cells. These findings highlight the OX40L axis as a key driver of T cell responses in AD.^6,7

Understand the disease burden of moderate-to-severe atopic dermatitis.

Abbreviations

AD, atopic dermatitis; TNF-α, tumor necrosis factor alpha; IL-4, interleukin 4; IL-13, interleukin 13; APC, antigen-presenting cell; IL-2, interleukin 2

References

1. Hansen-Sackey EB, Hartono S. Atopic dermatitis: Pathophysiology and emerging treatments. Allergies. 2025 Nov 10;5(4):40.
2. Croft M, Esfandiari E, Chong C, Hsu H, Kabashima K, Kricorian G, et al. OX40 in the pathogenesis of atopic dermatitis-A new therapeutic target. Am J Clin Dermatol. 2024 May 18;25(3):447–61.
3. Sadrolashrafi K, Guo L, Kikuchi R, Hao A, Yamamoto RK, Tolson HC, et al. An OX-Tra’Ordinary tale: The role of OX40 and OX40L in atopic dermatitis. Cells. 2024 Mar 28;13(7):587.
4. Tsoi LC, Rodriguez E, Stölzl D, Wehkamp U, Sun J, Gerdes S, et al. Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. J Allergy Clin Immunol. 2020 May 1;145(5):1406–15.
5. Guttman-Yassky E, Croft M, Geng B, Rynkiewicz N, Lucchesi D, Peakman M, et al. The role of OX40 ligand/OX40 axis signalling in atopic dermatitis. Br J Dermatol. 2024 Sep 18;191(4):488–96.
6. Furue M, Furue M. OX40L-OX40 signaling in atopic dermatitis. J Clin Med. 2021 Jun 11;10(12):2578.
7. Elsner JS, Carlsson M, Stougaard JK, Nygaard U, Buchner M, Fölster-Holst R, et al. The OX40 axis is associated with both systemic and local involvement in atopic dermatitis. Acta Derm Venereol. 2020 Mar 31;100(6):adv00099.
8. Facheris P, Jeffery J, Del Duca E, Guttman-Yassky E. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol. 2023 May 16;20(5):448–74.
9. Schettini N, Pacetti L, Corazza M, Borghi A. The role of OX40-OX40L axis in the pathogenesis of atopic dermatitis. Dermatitis. 2025 Jan 1;36(1):28–36.
10. Pan Y, Wang Y, Xu M, Zhong M, Peng X, Zeng K, et al. The roles of innate immune cells in atopic dermatitis. J Innate Immun. 2024 Jul 18;16(1):385–96.