Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation to encephalitogenic T cells.
Astrocytes are nonprofessional APCs that may participate in Ag presentation and activation of pathogenic CD4+ T cells involved in central nervous system (CNS) inflammatory diseases. Using immortalized pure astrocytes as a complement to the study of primary astrocytes, we investigated whether these astrocytes express elements involved in the class II endocytic pathway and if they are capable of processing native myelin basic protein (MBP), a step that could be necessary for initiating or perpetuating T cell recognition of this self-Ag in vivo. Upon IFN-gamma-stimulation, primary and immortalized astrocytes up-regulate class II transactivator (CIITA), invariant chain (Ii) (p31 and p41), H-2Ma, and H-2Mb. Analysis of CIITA cDNA sequences demonstrated that CIITA transcription in astrocytes is directed by a promoter (type IV) that mediates IFN-gamma-inducible CIITA expression and encodes a CIITA protein that differs in its N-terminal sequence from CIITA reported in professional APC. Comparing live and fixed APC for Ag presentation, we show that Ag processing by APC is required for presentation of native MBP to autopathogenic T cells specific for the major MBP epitope, Acl-11. We have observed that primary astrocytes and some, but not all, astrocyte lines in the absence of contaminating microglia are capable of processing and presenting native MBP, suggesting that there may be heterogeneity. Our study provides definitive evidence that astrocytes are capable of processing CNS autoantigen, indicating that astrocytes have potential for processing and presentation of CNS autoantigen to proinflammatory T cells in CNS autoimmune disease.
Soos
J M
JM
Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Morrow
J
J
Ashley
T A
TA
Szente
B E
BE
Bikoff
E K
EK
Zamvil
S S
SS
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D002417:Cattle; D002461:Cell Line, Transformed; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology*; D006681:HLA-D Antigens / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis
D000944:Antigens, Differentiation, B-Lymphocyte; D001324:Autoantigens; C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D004676:Myelin Basic Protein; D009687:Nuclear Proteins; D015534:Trans-Activators; C045084:invariant chain; D007371:Interferon-gamma