OX40-OX40L Signaling in T- Cell Function and Atopic Dermatitis

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OX40-OX40L represents a critical costimulatory immune checkpoint pathway essential for T-cell activation, where OX40 ligand on antigen-presenting cells interacts with OX40 receptors on T cells to provide necessary context for immune responses. These molecules are transiently expressed: OX40 ligand appears within 24 hours of antigen-presenting cell activation, and OX40 expression occurs 1 to 5 days after T-cell stimulation. This transient expression pattern normally guides T-cell differentiation, activation, polarization, memory cell formation, and regulatory T-cell control in healthy immune responses.

In atopic dermatitis and other T cell–mediated inflammatory diseases, sustained OX40-OX40L interaction perpetuation drives excessive effector phenotype development, increased cytokine production, enhanced T-cell activation, mobility, and survival while reducing regulatory phenotype expression. This creates an immune imbalance favoring overactivation with inadequate regulation, leading to long-lived inflammatory cell production. The pathway’s role extends beyond atopic dermatitis to conditions such as alopecia areata and inflammatory bowel disease, suggesting broad therapeutic potential for T cell–mediated inflammatory conditions.

Targeting the OX40-OX40L pathway offers a novel approach to address T cell–mediated immunity dysregulation by intervening earlier on in the immune cascade than cytokine-specific therapies. Rather than eliminating this essential immune function, therapeutic strategies aim to modulate the pathway’s overactivation while preserving normal immune responses. This approach could potentially provide broader therapeutic coverage across multiple T-cell subsets and inflammatory pathways, offering a more comprehensive treatment strategy for the immunologic heterogeneity observed in atopic dermatitis than single cytokine–targeting approaches.