OX40-Ligand: A Conductor of the Atopic Dermatitis Inflammatory Symphony?

April W. Armstrong, MD, MPH

Disclosure: This is a nonpromotional article for healthcare professionals and is sponsored by Sanofi. The author was compensated by Sanofi in connection with this article.

April W Armstrong has served as a research investigator, scientific advisor, or speaker to AbbVie, Amgen, Almirall, Arcutis, ASLAN, Beiersdorf, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho, Sun, Dermavant, Dermira, Sanofi, Takeda, Organon, Regeneron, and Pfizer.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathophysiology involving immune dysregulation and barrier dysfunction. Signs and symptoms of AD are the result of marked T-cell-mediated local and systemic inflammation.^1-3 Activation and subsequent expansion of effector T-cell subsets, including helper T 2 (Th2), Th1, Th17, and Th22, drive the heterogeneous inflammation characteristic of AD.^1,3,4 These activated effector T cells release inflammatory cytokines such as interleukin 4 (IL-4), IL-13, IL-17, and IL-31, which contribute to skin barrier disruption, epidermal thickening, and itch observed in AD.^2,5,6 OX40-Ligand (OX40L) is an induced upstream co-stimulatory signaling molecule that binds its receptor (OX40) on activated T cells, orchestrating the expansion of effector T cells by promoting proliferation, prolonged survival, and cytokine release.^1,2,5,7,8 The observation of increased expression of OX40L, its receptor (OX40), and the number of OX40-expressing cells in lesional skin vs. healthy skin in patients with AD indicates that this inducible signaling axis contributes to pathologic AD inflammation.^5,9 Here we unravel the role of OX40L in contributing to the initiation and chronic persistence of AD.

Introducing the inflammatory symphony: Conducted by OX40L and antigen-presenting cells

Cued by a conductor, the violins, violas, cellos, and woodwinds build on one another to amplify their instruments into one written score. Similarly, cells of the immune system are recruited and activated, amplifying the inflammatory score that drives AD.

A conductor - Professional antigen-presenting cells (APCs) and OX40L

Think of professional APCs, like dendritic cells, macrophages, and B cells, as conductors of the immune system. Just as a conductor interprets a musical score and guides the orchestra, APCs process foreign material, such as allergens, to initiate a targeted inflammatory response via presentation of processed allergen fragments to naïve T cells using major histocompatibility complex (MHC) class II.^1,2,10,11

APCs conduct an inflammatory response through the expression of several co-stimulatory (pro-inflammatory) and co-inhibitory (anti-inflammatory) molecules known as immune checkpoint molecules that modify the degree of T-cell activation.² OX40L is a co-stimulatory molecule primarily expressed by activated professional APCs and serves as an extension of the conductor.^2,8,12 OX40L is also expressed by nonprofessional APCs such as type 2 innate lymphoid cells (ILC2s), endothelial cells, and fibroblasts, which present antigens using MHC class I.^5,10,13 OX40L signals further instruct and fine-tune the immune response.^2,5,6

The strings - Effector helper T-cells

Effector T cells are like the string section of an orchestra, often carrying the main melody and harmonizing with other immune cells to drive the inflammatory response in AD. Just as different stringed instruments produce distinct sounds, helper T-cell subsets release various cytokines, each dictating the intensity and type of immune response.^2,4,5 Like an orchestra conductor guiding the strings, professional APCs conduct the activation and differentiation of naive T cells.^14,15 These naive T cells are differentiated into specialized helper T-cell subsets – Th1, Th2, Th17, and Th22 – each with a unique role to play in the symphony of AD inflammation.⁶ Once activated, these effector helper T-cell subsets upregulate expression of OX40, making them responsive to a conductor’s signals for survival, proliferation, and cytokine release.^2,14

The brass - Memory T-cells

Most effector helper T cells undergo apoptosis; however, some transition into long-lived memory T cells.^5,15 The memory T cells, much like the bold and powerful sounds created by the brass section, facilitate a faster and more robust immune response upon repeat exposure to antigens, quickly mobilizing other immune cells and promoting a swift inflammatory response.^5,15

The percussion - Regulatory T-cells

Just as percussion instruments provide rhythmic structure and layers of complexity to a musical piece, regulatory T cells (Tregs) regulate the inflammatory response.^2,16 They ensure the immune response doesn't become too chaotic or overwhelming, helping to keep pace by maintaining immune tolerance to allergens and preventing tissue damage.¹⁶

First movement - Initiation of OX40L signaling in AD

Reminiscent of an oboe that plays the tuning note and signals the start of the symphony, skin barrier dysfunction enables allergen penetration in AD. Allergens are then processed by and displayed on professional APCs for antigen recognition by T cells.^1,4,5,11 After antigen engagement by the T-cell receptor (TCR), interaction of the first co-stimulatory receptor−ligand pair expressed on APCs and T cells follows (e.g., CD40−CD40L and CD28−B7).^2,12,14,17 Prior to activation, APCs and naïve T cells do not ubiquitously express OX40L or OX40, respectively. This early-phase activation of T cells initiates the expression of the secondary co-stimulatory molecule OX40L on the surface of APCs within 24 hours. The expression of its receptor, OX40, soon follows within 1-5 days on the surface of activated T cells.^2,8,12 The binding of OX40L and its receptor orchestrates the dynamic symphony of immune response promoting T-cell proliferation and survival and cytokine release in AD.^2,18 Several signals control the extent of OX40L expression, including antigen stimulation, other co-stimulatory pathways, and alarmins such as thymic stromal lymphopoietin released from damaged epithelial cells.^2,12,19

With OX40L signaling, activated T cells clonally expand into effector T cells. Those effector T cells, particularly Th2 cells, secrete cytokines including IL-4 and IL-13 that downregulate the expression of crucial structural proteins in keratinocytes, such as filaggrin and loricrin. This downregulation, coupled with fibrosis due to increased collagen production driven by these cytokines, weakens the epidermal barrier and allows for increased allergen penetration.^1,5,6,11 Adding insult to injury, Th2 cells also release IL-31, a potent inducer of itch. This relentless urge to scratch further disrupts the already compromised epidermal barrier.⁶ Th2-driven inflammation is further potentiated by additional Type 2 cytokine-producing immune cells such as subcutis resident OX40L-expressing ILC2s that are found in elevated numbers in AD skin.^6,7 The complex inflammatory cascade triggers a potent feedback loop. Injured keratinocytes release more alarmins, activating the OX40L pathway, which in turn amplifies and sustains T-cell Type 2 and non-Type 2 inflammation.^1,2,5,7 Driven by OX40L signaling, the AD inflammatory symphony crescendos into a chronic state.

Figure 1:

Professional APCs and OX40L are critical for the activation and expansion of effector T cells in AD

After antigen engagement by the TCR, interaction of the first co-stimulatory receptor−ligand pair expressed on APCs and T cells follows (e.g., CD40−CD40L and CD80−CD28). The early phase of T-cell activation initiates the expression of the secondary co-stimulatory molecule OX40L on the surface of APCs. The expression of its receptor, OX40, soon follows on the surface of activated T cells. OX40L signaling drives expansion of effector T cells and suppresses Treg induction.⁵

AD, atopic dermatitis; APC, antigen-presenting cell; CD, cluster of differentiation; MHC II, major histocompatibility complex class II; OX40L, OX40-Ligand; TCR, T-cell receptor; TGF-B, transforming growth factor beta; Th, helper T cell; Treg, regulatory T cell.

A symphony stuck at fortissimo - OX40L signaling in the chronicity and recurrence of AD

The dissonant melodies of epidermal damage and immune dysregulation create a pro-inflammatory environment that sets the stage for a protracted inflammatory response. This pro-inflammatory environment orchestrated by OX40L signaling further amplifies the expansion of Th2 cells and triggers the recruitment of even more effector T cells to the site of damage.^6,7,14 In the chronic state of AD, other helper T-cell subsets, including Th1, Th17, and Th22 cells, are drawn into the inflammatory microenvironment.^5,7 These players amplify the noise; for instance, IL-22, primarily produced by Th22 cells, is associated with increased AD severity and drives keratinocyte proliferation, leading to the epidermal thickening (hyperplasia) characteristic of the disease.^6,7

Importantly, OX40L enables memory T-cell generation and inhibits regulatory T-cell function, which further contributes to AD pathogenesis.^2,5,7 OX40L signaling has also been shown to suppress the induction of Tregs, which attenuates their immune suppressor function.^5,20 The prolonged survival of effector T cells induced by OX40L signaling helps some of these cells to become resting memory T cells.^5,6,14 In AD, re-exposure of previously encountered antigens triggers the fast reactivation of resting memory T cells.^5,7,15 These memory T cells are then converted into effector memory T cells and rapidly express OX40. This process facilitates the release of pro-inflammatory cytokines and expansion of effector memory T cells.^5,7 OX40-expressing effector memory T cells are upregulated in AD lesions.^5,7 This suggests that the OX40L signaling axis plays an important role in the disease recurrence observed in AD.^5,7

Figure 2: The AD Inflammation Orchestra Conducted by the Professional APC and OX40-Ligand

AD inflammation is orchestrated by the activated APCs and OX40L. Like the strings of the orchestra, after initial activation effector T cells including Th2, Th1, Th17, and Th22 express OX40, making them responsive to a conductor’s signals for survival, proliferation, and cytokine release. OX40L signaling also suppresses the induction of Tregs, which attenuates their immune suppressor function. The prolonged survival of effector T cells induced by OX40L signaling helps some of these cells to become resting memory T cells.^2,5-7

AD, atopic dermatitis; APC, antigen-presenting cell; IFNγ, interferon gamma; IL, interleukin; OX40L, OX40-Ligand; Th, helper T cell; Tmem, memory T cell; TNF, tumor necrosis factor; Treg, regulatory T cell.

Finale

APCs and naïve T cells do not ubiquitously express OX40L or OX40, respectively; OX40L and OX40 expression is induced upon cell activation.^2,8 Upon induction, the OX40L signaling is an integral upstream signaling pathway that conducts multiple immune axes, contributing to the cycle of epidermal dysfunction and inflammation in AD pathogenesis.^5,7 AD is a dynamic, heterogeneous inflammatory disease that involves the activation of APCs and the subsequent expansion of multiple helper T-cell subsets.^3,4 The OX40L pathway suppresses the induction of Tregs, while also driving the expansion of antigen-specific helper T-cell subsets.^2,5,7,20 These helper T cells produce cytokines that mediate the burdensome signs and symptoms of AD.^1,5,7,11 Furthermore, the signaling pathway contributes to memory T-cell generation, which may enable AD disease recurrence.^5,7 Given the complexity of the underlying inflammation in patients with AD, an increased understanding of the OX40L pathway can improve our understanding of AD pathogenesis.⁶ Currently approved therapies largely target cytokine-specific pathways; however, the heterogeneity of AD underscores the need for therapeutic strategies that work upstream in the inflammatory cascade.^6,21,22

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