title: CD40/CD40L interaction is essential for the induction of EAE in the absence of CD28-mediated co-stimulation.
abstract: CD28 provides a co-stimulatory signal critical for optimal T cell activation. We and others have shown that the B7/CD28 co-stimulatory pathway is a major regulatory pathway for the control of immune responses. Experimentally induced models of autoimmunity have been shown to be prevented or reduced in intensity in mice deficient for CD28. Here, we show that EAE and accompanying neuroantigen-specific immune responses are drastically reduced in the absence of CD28. However, we go on to show that EAE can be induced in CD28-deficient mice following two immunizations. After re-immunization, CD28-deficient mice develop severe EAE with myelin-specific responses equal to those of wildtype controls, and extensive demyelination in the spinal cord. Treatment of CD28-deficient mice with anti-CD40L at the time of immunization significantly reduced DTH responses and prevented the development of EAE following two immunizations, indicating a critical role for CD40/CD40L signaling in the absence of CD28. Taken together, our results indicate that CD28-mediated co-stimulation does not regulate immunological anergy. Instead, CD28 appears to adjust the threshold for activation and expansion of autoreactive cells.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School and the Northwestern University Institute for Neuroscience, Chicago, IL 60611, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Girvin
authors.forename: Mauro C
authors.initials: MC
authors.lastname: Dal Canto
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006968:Hypersensitivity, Delayed; D007114:Immunization; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D019013:CD40 Antigens; D018076:DNA, Complementary; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D023201:CD40 Ligand