Regulation of Myeloid Derived Suppressor Cell (MDSC) dynamics by T regulatory cells

Abstract

Abstract Multiple sclerosis is an inflammatory demyelinating autoimmune disorder affecting the central nervous system whose severity is reduced using immune suppressive drugs. Therapeutic intervention with interferon-b reduces disease exacerbations and delays relapses. The receptor for type 1 interferon, IFNAR, is present on virtually all cell types making it difficult to dissect the mechanisms involved. We generated mice with a conditional deletion (cKO) of IFNAR in Treg cells (IFNARfl/flFoxp3cre). cKO mice developed severe EAE with an earlier onset than control mice. The activation status and effector cytokine production of CD4+ and CD8+ T cells in the draining lymph nodes (dLN) was similar in WT and cKO mice during the priming phase. Treg activation and expansion were also similar in WT and cKO mice. However, we noted a substantial reduction of myeloid derived suppressor cells (MDSCs) in the dLN of cKO mice while equivalent numbers of MDSCs were present in bone marrow and spleen of WT and cKO mice. IFNARfl/flLysMcre mice do not show a similar reduction in MDSC number indicating that the enhanced disease severity in the cKO mice is dependent on IFNAR signaling on Treg cells. CD4+ T cells from cKO mice were found to be defective in chemokine secretion suggesting that IFNAR signaling on Treg modulates the capacity of CD4+ T cells to secrete MDSC recruiting chemokines during the priming phase. While modulation of Treg number and function by MDSCs has been documented, this study is one of the first to demonstrate that Treg may modulate MDSC homing and raises the possibility of a novel role for Treg cells in regulating the kinetics of MDSC recruitment during inflammatory conditions. Supported by the Division of Intramural Research NIAID.