title: IL-2 suppression of IL-12p70 by a recombinant HSV-1 expressing IL-2 induces T-cell auto-reactivity and CNS demyelination.
abstract: To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8(+) and CD4(+) T cells contribute to HSV-IL-2-induced CNS demyelination with CD8(+) T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS.
authors.affiliation: Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Mandana
authors.initials: M
authors.lastname: Zandian
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Mott
authors.forename: Sariah J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.forename: Homayon
authors.initials: H
authors.lastname: Ghiasi
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000235:genetics; D020278:Demyelinating Autoimmune Diseases, CNS / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes / Q000502:physiology
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D018664:Interleukin-12