HLA‐DR‐restricted presentation of purified myelin basic protein is independent of intracellular processing

Antigen presentation to CD4+ T cells involves intracellular antigen processing and loading of peptides onto newly synthesized major histocompatibility complex (MHC)‐class II molecules. Some antigens, such as the lipid‐bound, native form of myelin basic protein (LB‐MBP) can also be presented by recycling of cell surface MHC class II molecules. The data reported here demonstrate that a preparation of highly purified, delipidated MBP (HP‐MBP) follows yet another presentation pathway. Similar to LB‐MBP, presentation of HP‐MBP to HLA‐DR1‐restricted T cells was independent of HLA‐DM, of newly synthesized proteins, and of invariant chain expression. However, in contrast to LB‐MBP, presentation of HP‐MBP was also independent of internalization of surface HLA‐DR molecules. The different requirements for the presentation of the two molecular forms of MBP were further confirmed by use of the protease inhibitor E64: presentation of LB‐MBP but not of HP‐MBP was inhibited after treatment of target cells with E64. Furthermore, intact HP‐MPB bound to isolated HLA‐DR molecules in vitro with an association rate that was considerably faster than that of short peptides. These results show that presentation of HP‐MBP is independent of intracellular processing and suggest that it may be presented to T cells by direct binding to surface HLA‐DR molecules.

[1]  M. Sela,et al.  Synthetic Copolymer I and Myelin Basic Protein Do Not Require Processing Prior to Binding to Class II Major Histocompatibility Complex Molecules on Living Antigen-Presenting Cells , 1995 .

[2]  Jeffrey A. Shaman,et al.  An essential role for HLA–DM in antigen presentation by class II major histocompatibility molecules , 1994, Nature.

[3]  J. Berzofsky,et al.  Antigen conformation determines processing requirements for T-cell activation. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. D. Robinson,et al.  Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87-106. , 1992, Journal of immunology.

[5]  P. Riccio,et al.  A new detergent to purify CNS myelin basic protein isoforms in lipid-bound form. , 1994, Neuroreport.

[6]  H. McFarland,et al.  Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. , 1995, Critical reviews in clinical laboratory sciences.

[7]  R. Martenson,et al.  Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. , 1972, Preparative biochemistry.

[8]  Carol Readhead,et al.  Expression of a myelin basic protein gene in transgenic shiverer mice: Correction of the dysmyelinating phenotype , 1987, Cell.

[9]  E. Unanue,et al.  Differential requirements for antigen processing by macrophages for lysozyme-specific T cell hybridomas. , 1984, Journal of immunology.

[10]  A. Lanzavecchia,et al.  Processed antigen binds to newly synthesized mhc class II molecules in antigen-specific B lymphocytes , 1991, Cell.

[11]  P. Riccio,et al.  A new procedure for the isolation of the brain myelin basic protein in a lipid‐bound form , 1984, FEBS letters.

[12]  T. Watts,et al.  MHC class II-restricted presentation of native protein antigen by B cells is inhibitable by cycloheximide and brefeldin A. , 1990, Journal of immunology.

[13]  R. Demars,et al.  Homozygous deletions that simultaneously eliminate expressions of class I and class II antigens of EBV-transformed B-lymphoblastoid cells. I. Reduced proliferative responses of autologous and allogeneic T cells to mutant cells that have decreased expression of class II antigens. , 1984, Human immunology.

[14]  Eric O Long,et al.  Presentation of cytosolic antigen by HLA-DR requires a function encoded in the class II region of the MHC. , 1993, Journal of immunology.

[15]  G. M. Liuzzi,et al.  Lipid-bound, native-like, myelin basic protein. Batch-wise preparation and perspectives for use in demyelinating diseases. , 1990, Molecular and chemical neuropathology.

[16]  M. Sela,et al.  Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Eric O Long,et al.  Two processing pathways for the MHC class II-restricted presentation of exogenous influenza virus antigen. , 1994, Journal of immunology.

[18]  U. Krzych,et al.  Plasmodium berghei‐specific T cells respond to non‐processed sporozoites presented by B cells , 1993, European journal of immunology.

[19]  Eric O Long,et al.  Antigen presentation mediated by recycling of surface HLA-DR molecules , 1995, Nature.

[20]  C. Benoist,et al.  Mice lacking the MHC class II-associated invariant chain , 1993, Cell.

[21]  A. Chervonsky,et al.  The requirement for DM in class II-restricted antigen presentation and SDS-stable dimer formation is allele and species dependent , 1995, The Journal of experimental medicine.

[22]  L. Amaducci,et al.  Antibodies specific for the lipid-bound form of myelin basic protein during experimental autoimmune encephalomyelitis , 1993, Journal of Neuroimmunology.

[23]  R. Germain,et al.  Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression , 1993, The Journal of experimental medicine.

[24]  H. Erlich,et al.  Molecular analysis of HLA class I and class II antigen loss mutants reveals a homozygous deletion of the DR, DQ, and part of the DP region: implications for class II gene order. , 1986, Human immunology.

[25]  N. Ling,et al.  Isolation, primary structure, and synthesis of human hypothalamic somatocrinin: growth hormone-releasing factor. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[26]  L Adorini,et al.  Capacity of intact proteins to bind to MHC class II molecules. , 1989, Journal of immunology.

[27]  C. Benoist,et al.  Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. , 1994, Science.

[28]  Lipid‐Bound, Native‐Like, Myelin Basic Protein: A Weil‐Known Protein in a New Guise, Or an Unlikely Story? , 1993, Journal of neurochemistry.

[29]  H. Kalbacher,et al.  Self and foreign peptides interact with intact and disassembled MHC class II antigen HLA-DR via tryptophan pockets. , 1991, Biochemistry.

[30]  H. Rammensee,et al.  Ligand motifs of HLA-DRB5*0101 and DRB1*1501 molecules delineated from self-peptides. , 1994, Journal of immunology.

[31]  C. Deber,et al.  The structure and function of central nervous system myelin. , 1993, Critical reviews in clinical laboratory sciences.

[32]  P. Allen,et al.  T cell recognition of fibrinogen. A determinant on the A alpha-chain does not require processing. , 1988, Journal of immunology.

[33]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[34]  H. Kalbacher,et al.  Self-peptides from four HLA-DR alleles share hydrophobic anchor residues near the NH2-terminal including proline as a stop signal for trimming. , 1993, Journal of immunology.

[35]  L. Amaducci,et al.  Induction of experimental autoimmune encephalomyelitis in rats and immune response to myelin basic protein in lipid-bound form , 1993, Journal of the Neurological Sciences.

[36]  R. Smith,et al.  The Basic Protein of CNS Myelin: Its Structure and Ligand Binding , 1992, Journal of neurochemistry.

[37]  S. Ceman,et al.  DMA and DMB are the only genes in the class II region of the human MHC needed for class II-associated antigen processing. , 1995, Journal of immunology.

[38]  Eric O Long,et al.  MHC class II deletion mutant expresses normal levels of transgene encoded class II molecules that have abnormal conformation and impaired antigen presentation ability. , 1992, Journal of immunology.

[39]  B. Arp,et al.  HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells , 1994, Nature.