CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis.
Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.
Oliveira-dos-Santos
A J
AJ
Amgen Institute, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Ho
A
A
Tada
Y
Y
Lafaille
J J
JJ
Tonegawa
S
S
Mak
T W
TW
Penninger
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D001324:Autoantigens; D018106:CD28 Antigens; D016207:Cytokines; D004676:Myelin Basic Protein