title: Depletion of CD4+ CD25+ regulatory T cells confers susceptibility to experimental autoimmune encephalomyelitis (EAE) in GM-CSF-deficient Csf2-/- mice.
abstract: Previous studies established that GM-CSF-deficient (Csf2-deficient) mice exhibit profound resistance to experimental autoimmune encephalomyelitis. This study addressed whether the resistance of Csf2-deficient mice was a result of a requirement for GM-CSF in controlling the functional balance between effector and regulatory T cell subsets during experimental autoimmune encephalomyelitis. The main observation was that treatment with the anti-CD25 mAb PC61 rendered Csf2-deficient mice fully susceptible to severe, chronic experimental autoimmune encephalomyelitis, with disease incidences and severities equivalent to that of C57BL/6 mice. When both donors and recipients were treated with PC61 in a passive model of experimental autoimmune encephalomyelitis, adoptive transfer of myelin-specific Csf2-deficient T cells into Csf2-deficient recipients resulted in a nonresolving chronic course of severe paralytic experimental autoimmune encephalomyelitis. The peripheral Csf2-deficient T cell repertoire was marked by elevated CD3+T cell frequencies that reflected substantial accumulations of naïve CD44null-lowCD4+and CD8+T cells but essentially normal frequencies of CD4+CD25+forkhead box P3+T cells among the CD3+T cell pool. These findings suggested that Csf2-deficient mice had secondary deficiencies in peripheral T cell sensitization to environmental antigens. In accordance, myelin oligodendrocyte glycoprotein 35-55/CFA-sensitized Csf2-deficient mice exhibited deficient peripheral sensitization to myelin oligodendrocyte glycoprotein, whereas pretreatment of Csf2-deficient mice with PC61 enabled the robust induction of myelin oligodendrocyte glycoprotein-specific T cell responses in the draining lymphatics. In conclusion, the experimental autoimmune encephalomyelitis resistance of Csf2-deficient mice, at least in part, reflects a deficient induction of effector T cell function that cannot surmount normal regulatory T cell barriers. Experimental autoimmune encephalomyelitis effector responses, however, are unleashed upon depletion of regulatory CD25+T cells.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA; and.
authors.forename: Debjani
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA; and.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Curtis
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA; and.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wilkinson
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA; and The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative Disease Research, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA manniem@ecu.edu.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mannie
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000502:physiology; D006098:Granulocytes / Q000276:immunology; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000276:immunology; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053645:Interleukin-2 Receptor alpha Subunit; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: FOXP3+ T cells; multiple sclerosis; neuroimmunology; tolerance