Immune Pathways Driving T Cell Inflammation in Atopic Dermatitis

AD extends beyond the traditional Th2 pathway, involving complex dysregulation across Th1, Th17, and Th22 subsets. This dysregulation involves drivers including the OX40L pathway, that initiates T-cell expansion and immune responses.^2,5

There is heterogeneity across AD endotypes, including the fact that immune signatures differ by age, disease chronicity and race.² This also outlines how persistent effector and memory T cells survive in the skin and overwhelm regulatory mechanisms, driving rapid relapse upon trigger exposure.⁵

While many current treatments have made great strides in improving patient outcomes in AD, there still exists an unmet need. Many treatments take an approach of selectively targeting type 2 inflammatory drivers, addressing only part of the immune activity involved in AD.⁴

The Inflammatory Prequel: Driving T Cell Inflammation in Atopic Dermatitis

The "inflammatory prequel" is a foundational driver of immune imbalance characterizing AD. The term refers to an initiating phase of AD immune dysregulation, in the context of antigen presentation and T-cell co-stimulation, characterized by the activation, differentiation, proliferation, and survival of T cells.⁴ In AD, OX40L signaling during the inflammatory prequel contributes to the persistent immune activation that serves as a key contributor to the chronic and recurrent nature of the disease.⁴  

Role of Antigen Presenting Cells (APCs) in Atopic Dermatitis

The activity of antigen-presenting cells in the skin (e.g., Langerhans cells) is essential to the early stages of T cell inflammation. Antigen stimulation on effector and memory T cells causes the OX40 receptor (OX40R) to be expressed. When the OX40 ligand (OX40L), which is carried by APCs, binds to OX40R, it activates signaling pathways that drive inflammation in AD.⁶ 

Role of the OX40L pathway in Atopic Dermatitis

The OX40L co-stimulatory pathway is a pivotal driver that can augment the T cell response.⁴ Once activated this pathway increases effector T cell proliferation and survival, promotes memory T cells, suppresses the formation and attenuates the function of regulatory T cells, and increases the production of cytokines. This results in a never-ending inflammatory cycle, a chronic itch and a dysfunctional skin barrier.^4,6 

Learn more about the OX40L/OX40R pathway in AD. 
 

Role of Effector, Memory, and Regulatory T Cells in Atopic Dermatitis

The activity of OX40L drives the proliferation of effector T cells and the formation of memory T cells, meaning that the inflammatory cycle may be sustained even when patients appear to be controlled.⁶ The respective quantities of effector, memory and regulatory T cells are designed to regulate the immune response appropriately. However, in AD, the effects of OX40L signaling after antigen stimulation create an imbalance in these systems.

• Effector T cells: target infected cells and regulate the immune response through the production of cytokines.⁷ In AD, the activation, proliferation and survival of these cells lead to persistent inflammation and contributes to flare activity.⁸
• Memory T cells: remember responses to past infections to protect against future reinfections.⁹ In AD, the generation of memory T cells contributes to the chronic and recurrent nature of the disease, as these cells are converted into effector T cells upon antigen re-exposure.⁴
• Regulatory T cells: maintain immune homeostasis and self-tolerance.¹⁰ In AD, the activation of the OX40L pathway causes reduced numbers or impaired function of these cells, leading to failure to control reactions to antigens and contributing to chronic inflammation.⁸

The Diversity of Inflammatory Cytokines in Atopic Dermatitis

AD is a T-cell-mediated condition that can be driven by multiple inflammatory subsets, including Th2, Th1, Th17, and Th22, which release distinct cytokines that shape chronicity and skin barrier dysfunction.² The mechanisms behind the condition can vary from one patient to another. For instance, AD can be caused by type 2 or non-type-2 inflammation.^1,2 

Understanding AD Disparities Through T Cell Signatures

The heterogeneity of AD goes beyond disease phenotype to underlying mechanisms, including T cell signatures. 

AD is driven by various effector T-cell subsets that release a range of cytokines related to inflammation, chronicity, and immune responses.^1,2 Part of the complexity of AD is due to each patient presenting a unique combination of inflammatory drivers across Th2, Th1, Th17, and Th22 pathways.^1,2 

The complexity of these immune signatures in AD contributes to the unpredictability and variability observed in treatment responses, reinforcing the need to consider a wider range of immune drivers than only the type 2 pathways when understanding AD.²

Notably, studies have also shown variations in T cell and inflammatory activity across racial groups.^2,11,12 Asian patient cohorts generally exhibit increased Th17 signals, African American patients often show amplified Th2/Th22 activity, and European patients skew towards greater Th2 activity.^2,12,13 This variation in T cell signatures across patient groups further supports the need to shift from the "one size fits all" approach.¹¹

The Cycle of AD Chronicity: Immune Imbalance and Memory

AD is a chronic, relapsing condition.¹ Through the recurrent exposure to antigens and the engagement of co-stimulatory signaling (e.g., OX40L/OX40R), an increasing amount of memory T cells get differentiated into resident memory T cells (TRM) - cells that survive in the skin beyond active flares.^6,14 

These TRM cells exhibit marked effector functions including the rapid secretion of pro-inflammatory cytokines. When these cells are persistently activated, they exert persistent inflammatory effects. Alongside other features of immune dysregulation in AD, this persistent inflammatory activity can overwhelm the body’s regulatory mechanisms (particularly regulatory T cells), leading to loss of immune homeostasis.¹⁴

The failure of regulatory T cells to adequately suppress the activity of these effector cells leads to a dysregulated immune response, contributing to a shift toward an effector-dominated environment.^4,14 The TRM cells allow the effector T cells to rapidly re-engage the inflammatory response upon subsequent antigen re-exposure, trapping patients in a cycle of recurrent AD.¹⁴

Unmet Needs Remaining with Targeting Effector Cytokines in Atopic Dermatitis

While current treatments have significantly improved outcomes in AD, unmet needs remain. Many existing therapies selectively target individual inflammatory pathways or cytokines, not accounting for the molecular heterogeneity of the disease.^15–17 

Cytokine-targeted therapies have shown success in providing symptom relief to many AD patients, however, they may leave drivers of inflammation and memory T cells intact, and often require continuous treatment to prevent recurrence, with long-term impacts on patients’ lives.^18–20 

The treatment landscape of AD has evolved with the identification of different immunological targets under investigation, with treatment goals shifting from alleviating symptoms to treating the underlying causes of the disease.^16,21 

Learn more about patient burden and unmet need in AD. 

Abbreviations

AD, atopic dermatitis; APC, antigen presenting cells; IL, interleukin; T, thymus-derived; Th, T helper.

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