Type I IFNs modulate T effector (Teff) and T regulatory (Treg) cell function during experimental autoimmune encephalomyelitis (EAE) (IRC4P.485)

Type I IFNs (IFNα and IFNβ) are a family of cytokines that mediate multiple roles in inflammation and autoimmunity. Previous studies have demonstrated that Type I IFNs primarily act on myeloid cells during the course of EAE. We have re-examined the role of Type I IFNs in EAE by generating mixed bone marrow chimeras between wild type (WT) mice and mice with a deficiency in the IFN receptor (IFNAR-/-). IFN plays a role in the T lymphocyte homeostasis as the ratio of WT to IFNAR-/- CD4+ T cells is skewed toward WT and the skewing is more marked in the Treg compartment. Surprisingly, after induction of EAE, the ratio of WT to IFNAR-/- T cells is reversed in the periphery and the mixed chimeras develop more severe disease than the WT/WT chimeras. Almost all of the CD4+Foxp3- and CD4+Foxp3+ T cells in the CNS of chimeric mice are derived from the IFNAR-/- donor, but the percentage of Foxp3+ T cells was similar in WT/WT and WT/IFNAR-/- chimeras. Both CD4+Foxp3- and CD4+Foxp3+ T cells from the IFNAR-/- donor expressed higher levels of α4 integrins, which may account for their increased numbers in the CNS during EAE. Mice with a conditional deletion of the IFNAR in Treg rapidly developed a very severe form of EAE. Taken together, these results demonstrate that signaling via the IFNAR is required for Treg suppressor function in EAE and that IFNAR signaling may also modulate homing of Teff cells to the CNS and/or their susceptibility to suppression by Treg.