Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity.
The role of processing in antigen (Ag) presentation and T cell activation in experimental allergic encephalomyelitis (EAE) was evaluated in wild-type mice, mice that selectively express either Ii p31 or p41, and mice completely deficient in Ii or H-2M. We demonstrate that processing of myelin oligodendrocyte glycoprotein (MOG) is required for presentation of the dominant encephalitogenic MOG epitope, p35-55. Ii p31- and p41-expressing mice developed EAE with similar incidence to wild-type mice, although p41 mice had a more severe course. Ag-presenting cells (APCs) from Ii- or H-2M-deficient mice could present p35-55, but not MOG, demonstrating that these APCs could not process native MOG. Ii- and H-2M-deficient mice were not susceptible to EAE by immunization with p35-55 or MOG or by adoptive transfer of encephalitogenic T cells. However, CD4+ T cells from p35-55-immunized H-2M-deficient mice proliferated, secreted IFN-gamma, and transferred EAE to wild-type, but not H-2M-deficient, mice. Thus, EAE resistance in H-2M-deficient mice is not due to an inability of APCs to present p35-55, or an intrinsic defect in the encephalitogenic T cell repertoire, but reflects a defect in APC function. Our results indicate that processing is required for initial Ag presentation and CNS T cell activation and suggest that autopathogenic peptides of CNS autoantigen may not be readily available for presentation without processing.
Slavin
A J
AJ
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Soos
J M
JM
Stuve
O
O
Patarroyo
J C
JC
Weiner
H L
HL
Fontana
A
A
Bikoff
E K
EK
Zamvil
S S
SS
D000818:Animals; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D001324:Autoantigens; D018076:DNA, Complementary; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; C045084:invariant chain