Macrophage IL-12p70 signaling prevents HSV-1-induced CNS autoimmunity triggered by autoaggressive CD4⁺ tregs

PURPOSE. CD4⁺CD25⁺FoxP3⁺ naturally occurring regulatory T cells (Tregs) maintain self-tolerance and function to suppress overly exuberant immune responses. However, it is unclear whether innate immune cells modulate Treg function. Here the authors examined the role of innate immunity in lymphomyeloid homeostasis. METHODS. The involvement of B cells, dendritic cells (DCs), macrophages, natural killer (NK) cells, and T cells in central nervous system (CNS) demyelination in different strains of mice infected ocularly with herpes simplex virus type 1 (HSV-1) was investigated. RESULTS. The authors found that depletion of macrophages, but not DCs, B cells, NK cells, CD4⁺ T cells, or CD8⁺ T cells, induced CNS demyelination irrespective of virus or mouse strain. As with macrophage depletion, mice deficient in interleukin (IL)-12p35 or IL-12p40 showed CNS demyelination after HSV-1 infection, whereas demyelination was undetectable in HSV-1-infected, IL-23p19-deficient, or Epstein-Barr virus-induced gene 3-deficient mice. Demyelination could be rescued in macrophage-depleted mice after the injection of IL-12p70 DNA and in IL-12p35^-/- or IL-12p40^-/- mice after injection with IL-12p35 or IL-12p40 DNA or with recombinant viruses expressing IL-12p35 or IL-12p40. Using FoxP3-, CD4-, CD8-, or CD25-depletion and gene-deficient mouse approaches, the authors demonstrated that HSV-1-induced demyelination was blocked in the absence of CD4, CD25, or FoxP3 in macrophage- depleted mice. Flow cytometry showed an elevation of CD4⁺CD25⁺FoxP3⁺ T cells in the spleens of infected macrophage- depleted mice, and adoptive transfer of CD4⁺CD25⁺ T cells to infected macrophage-depleted severe combined immunodeficient mice induced CNS demyelination. CONCLUSIONS. The authors demonstrated that macrophage IL- 12p70 signaling plays an important role in maintaining immune homeostasis in the CNS by preventing the development of autoaggressive CD4⁺ Tregs.