Abstract
The ability of CD4+Foxp3+ regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7+CCR5− lymph node-seeking to a CCR7−CCR5+ inflammation-seeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.
Highlights
CD4+Foxp3+ regulatory T-cells (Tregs) are essential for the maintenance of immunological homeostasis and self tolerance [1]
Transfer of Foxp3depleted Thy1.2+ CD4+ T-cells from DEREG mice into Thy1.1 mice revealed that the increase in IL-10 production and Treg number three days after CD28SA treatment is mainly the result of expansion of pre-existing Treg cells, rather than conversion from CD4+ Tconv (Fig. 1D)
We report that Tregs polyclonally activated with CD28SA in vivo dramatically expand in numbers, and initiate IL-10 production and upregulate effector molecules and homing receptors guiding them to inflamed tissue
Summary
CD4+Foxp3+ regulatory T-cells (Tregs) are essential for the maintenance of immunological homeostasis and self tolerance [1]. They control unwanted immune responses by a number of distinct mechanisms, which differentially contribute to suppression depending on the experimental settings studied [2]. IL-2 produced by ‘‘conventional’’ T-cells (Tconvs) drives Treg expansion and boosts regulatory function, including production of the suppressive cytokine IL-10 [3]. IL-10 produced by several innate and adaptive immune cells is a key immunosuppressive and anti-inflammatory cytokine as illustrated by the spontaneous lethal inflammatory bowel disease of IL10-deficient mice [6]. Foxp3+ Treg derived IL-10 contributes to immune regulation in vivo, not in all settings studied [2]. Selective IL-10 deficiency in Tregs results in spontaneous colitis and inflammation in skin and lung [9]
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