CD45Rb-low effector T cells require IL-4 to induce IL-10 in FoxP3 Tregs and to protect mice from inflammation

CD4(+) effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (Rb(Lo)Tem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of FoxP3 expression, the canonical transcription factor found in most regulatory T cells. In this report, we show that Rb(Lo)Tem cells can suppress inflammation by influencing Treg behavior. Co-culturing activated Rb(Lo)Tem and Tregs induced high expression of IL-10 in vitro, and conditioned media from Rb(Lo)Tem cells induced IL-10 expression in FoxP3(+) Tregs in vitro and in vivo, indicating that Rb(Lo)Tem cells communicate with Tregs in a cell-contact independent fashion. Transcriptomic and multi-analyte Luminex data identified both IL-2 and IL-4 as potential mediators of Rb(Lo)Tem-Treg communication, and antibody-mediated neutralization of either IL-4 or CD124 (IL-4Ra) prevented IL-10 induction in Tregs. Moreover, isolated Tregs cultured with recombinant IL-2 and IL-4 strongly induced IL-10 production. Using house dust mite (HDM)-induced airway inflammation as a model, we confirmed that the in vivo suppressive activity of Rb(Lo)Tem cells was lost in IL-4-ablated Rb(Lo)Tem cells. These data support a model in which Rb(Lo)Tem cells communicate with Tregs using a combination of IL-2 and IL-4 to induce robust expression of IL-10 and suppression of inflammation.