Dendritic cells control CD4+CD25+ Treg cell function in vitro through juxtacrine delivery of IL-2. (50.3)

Abstract

Abstract CD4+CD25+ regulatory T cells (Tregs) require IL-2 for their expansion and function. Unable to produce IL-2, Tregs rely on IL-2 from a neighboring cell. We explored whether DCs might serve as an important source of IL-2 for Tregs. Though a minor subset of DCs make IL-2, the IL-2 producing DCs were preferentially found in conjugate formation with Tregs. DCs continued to transcribe IL-2 in the presence of Tregs, but protein secretion was completely diverted to the Treg. Uptake of DC-derived IL-2 by Tregs involved cell:cell contact and CD25. DC IL-2 increased Tregs levels of CD25 and foxp3. Surprisingly, Treg suppressor function in vitro depended on DC IL-2. Tregs in cultures with WT DCs suppressed proliferation of CD4+ Teff more effectively than Tregs in cultures with IL-2 KO DCs. Tregs also suppressed IL-2 secretion by CD4+ Teff if cultured with WT DCs but showed no suppression if cultured with IL-2 KO DCs. In the later cultures, the transient addition of IL-2 at levels ≥ 500 U/ml restored Treg suppressor function, suggesting that DC to Treg delivery of IL-2 was spatially controlled to achieve locally high concentrations of IL-2. The findings demonstrate a clear requirement for DC-derived IL-2 for optimal Treg suppressor function in vitro and reveal a novel model of juxtacrine delivery of IL-2 from DCs to Tregs. The data lead us to speculate that IL-2 producing DCs may play a role in initiating the activation of functional Tregs in vivo through spatial delivery of signal 3.