Abstract
The presence of regulatory T cells (Tregs) in skin is important in controlling inflammatory responses in this peripheral tissue. Uninflamed skin contains a population of relatively immotile Tregs often located in clusters around hair follicles. Inflammation induces a significant increase both in the abundance of Tregs within the dermis, and in the proportion of Tregs that are highly migratory. The molecular mechanisms underpinning Treg migration in the dermis are unclear. In this study we used multiphoton intravital microscopy to examine the role of RGD-binding integrins and signalling through phosphoinositide 3-kinase P110δ (PI3K p110δ) in intradermal Treg migration in resting and inflamed skin. We found that inflammation induced Treg migration was dependent on RGD-binding integrins in a context-dependent manner. αv integrin was important for Treg migration 24 hours after induction of inflammation, but contributed to Treg retention at 48 hours, while β1 integrin played a role in Treg retention at the later time point but not during the peak of inflammation. In contrast, inhibition of signalling through PI3K p110δ reduced Treg migration throughout the entire inflammatory response, and also in the absence of inflammation. Together these observations demonstrate that the molecular mechanisms controlling intradermal Treg migration vary markedly according to the phase of the inflammatory response.
Highlights
CD4+ regulatory T cells (Tregs) are recognized for their capacity to control inappropriate activity of the immune system both systemically, and in peripheral sites [1,2,3]
Using MP-IVM, we found that RGD-binding integrins contributed to intradermal Treg migration to variable degrees, according to the phase of the inflammatory response, while signalling through the phosphoinositide 3-kinase (PI3K) p110d subunit was important for Treg motility under both resting and inflamed conditions
We investigated potential RGD-binding integrins responsible for intradermal Treg migration during contact hypersensitivity (CS), focusing on the av integrin found previously to be critical for effector CD4+ T cell migration in inflamed skin [14]. av integrin inhibition at 24 hours CS resulted in significant decreases in Treg average velocity (Figures 4A, B, Supplementary Video 4) and displacement
Summary
CD4+ regulatory T cells (Tregs) are recognized for their capacity to control inappropriate activity of the immune system both systemically, and in peripheral sites [1,2,3]. While Tregs have powerful systemic effects, in many cases suppression of inflammation in the periphery is dependent on the local actions of Tregs in these sites. While studies of conventional effector CD4+ T cells in models of skin infection have demonstrated that efficient intradermal migration is critical for effective anti-microbial function [14], the requirement for Treg migration throughout the skin in resolution of skin inflammation is unclear. To test this idea, it is first necessary to understand the molecular basis of this response
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