4 1BB Signaling in Conventional T Cells Drives IL 2 Production That Overcomes CD4+CD25+FoxP3+ T Regulatory Cell Suppression
Costimulation with the recombinant SA 4 1BBL agonist of 4 1BB receptor on conventional CD4+ T cells (Tconvs) overcomes the suppression mediated by naturally occurring CD4+CD25+FoxP3+ T regulatory cells (Tregs) The mechanistic basis of this observation has remained largely unknown. Herein we show that Tconvs, but not Tregs, are the direct target of SA 4 1BBL mediated evasion of Treg suppression. IL 2 produced by Tconvs in response to 4 1BB signaling is both necessary and sufficient for overcoming Treg suppression. Supernatant from Tconvs stimulated with SA 4 1BBL contains high levels of IL 2 and overcomes Treg suppression in ex vivo Tconv:Treg cocultures. Removal of IL 2 from such supernatant restores Treg suppression and repletion of Tconv:Treg cocultures with exogenous recombinant IL 2 overcomes suppression. This study establishes 4 1BB signaling as a key circuit that regulates physical and functional equilibrium between Tregs and Tconvs with important implications for immunotherapy for indications where a fine balance between Tregs and Teffs plays a decisive role.
PloS one