scholarly journals A polyalanine peptide with only five native myelin basic protein residues induces autoimmune encephalomyelitis.

1992 ◽  
Vol 176 (2) ◽  
pp. 605-609 ◽  
Author(s):  
A M Gautam ◽  
C I Pearson ◽  
D E Smilek ◽  
L Steinman ◽  
H O McDevitt
Keyword(s):  
T Cell ◽  
Myelin Basic Protein ◽  
Mhc Class Ii ◽  
Basic Protein ◽  
Class Ii ◽  
Autoimmune Encephalomyelitis ◽  
T Cell Stimulation ◽  
Disease Induction ◽  
Mhc Class Ii Molecules

The minimum structural requirements for peptide interactions with major histocompatibility complex (MHC) class II molecules and with T cell receptors (TCRs) were examined. In this report we show that substituting alanines at all but five amino acids in the myelin basic protein (MBP) peptide Ac1-11 does not alter its ability to bind A alpha uA beta u (MHC class II molecules), to stimulate specific T cells and, surprisingly, to induce experimental autoimmune encephalomyelitis (EAE) in (PL/J x SJL/J)F1 mice. Most other amino acid side chains in the Ac1-11 peptide are essentially irrelevant for T cell stimulation and for disease induction. Further analysis revealed that binding to A alpha uA beta u occurred with a peptide that consists mainly of alanines and only three of the original residues of Ac1-11. Moreover, when used as a coimmunogen with MBP Ac1-11, this peptide inhibited EAE. The finding that a specific in vivo response can be generated by a peptide containing only five native residues provides evidence that disease-inducing TCRs recognize only a very short sequence of the MHC-bound peptide.

scholarly journals Multiple discrete encephalitogenic epitopes of the autoantigen myelin basic protein include a determinant for I-E class II-restricted T cells.

1988 ◽  
Vol 168 (3) ◽  
pp. 1181-1186 ◽  
Author(s):  
S S Zamvil ◽  
D J Mitchell ◽  
M B Powell ◽  
K Sakai ◽  
J B Rothbard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Cell Clone ◽  
Class Ii ◽  
T Cell Epitopes ◽  
Intact Mouse ◽  
T Cell Clone

Immunization with the autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE). Initial investigations indicated that encephalitogenic murine determinants of MBP were located only within MBP 1-37 and MBP 89-169. Encephalitogenic T cell epitopes within these fragments have been identified. Each epitope is recognized by T cells in association with separate allelic I-A molecules. A hybrid I-E-restricted T cell clone that recognizes intact mouse (self) MBP has been examined. The epitope recognized by this clone includes MBP residues 35-47. When tested in vivo, p35-47 causes EAE. T cell recognition of p35-47 occurs only in association with I-E molecules. These results provide the first clear example that antigen-specific T cells restricted by I-E class II molecules participate in murine autoimmune disease. Furthermore, it is clear that there are multiple (at least three) discrete encephalitogenic T cell epitopes of this autoantigen, each recognized in association with separate allelic class II molecules. These results may be relevant to human autoimmune diseases whose susceptibility is associated with more than one HLA-D molecule.

scholarly journals Replacement of Pre-T Cell Receptor Signaling Functions by the CD4 Coreceptor

1997 ◽  
Vol 185 (1) ◽  
pp. 121-130 ◽  
Author(s):  
Anne M. Norment ◽  
Katherine A. Forbush ◽  
Nhan Nguyen ◽  
Marie Malissen ◽  
Roger M. Perlmutter
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
Experimental Manipulation ◽  
Thymocyte Development ◽  
Β Chain ◽  
Mhc Class Ii Molecules

An important checkpoint in early thymocyte development ensures that only thymocytes with an in-frame T cell receptor for antigen β (TCR-β) gene rearrangement will continue to mature. Proper assembly of the TCR-β chain into the pre-TCR complex delivers signals through the src-family protein tyrosine kinase p56lck that stimulate thymocyte proliferation and differentiation to the CD4+CD8+ stage. However, the biochemical mechanisms governing p56lck activation remain poorly understood. In more mature thymocytes, p56lck is associated with the cytoplasmic domain of the TCR coreceptors CD4 and CD8, and cross-linking of CD4 leads to p56lck activation. To study the effect of synchronously inducing p56lck activation in immature CD4−CD8− thymocytes, we generated mice expressing a CD4 transgene in Rag2−/− thymocytes. Remarkably, without further experimental manipulation, the CD4 transgene drives maturation of Rag2−/− thymocytes in vivo. We show that this process is dependent upon the ability of the CD4 transgene to bind Lck and on the expression of MHC class II molecules. Together these results indicate that binding of MHC class II molecules to CD4 can deliver a biologically relevant, Lck-dependent activation signal to thymocytes in the absence of the TCR-α or -β chain.

scholarly journals Early Endosomes Are Required for Major Histocompatiblity Complex Class II Transport to Peptide-loading Compartments

1999 ◽  
Vol 10 (9) ◽  
pp. 2891-2904 ◽  
Author(s):  
Valérie Brachet ◽  
Gérard Péhau-Arnaudet ◽  
Catherine Desaymard ◽  
Graça Raposo ◽  
Sebastian Amigorena
Keyword(s):  
Mhc Class Ii ◽  
Class Ii ◽  
Endocytic Pathway ◽  
Cross Linking ◽  
Histocompatibility Complex ◽  
Early Endosomes ◽  
Peptide Loading ◽  
Golgi Network ◽  
Mhc Class Ii Molecules

Antigen presentation to CD4+ T lymphocytes requires transport of newly synthesized major histocompatibility complex (MHC) class II molecules to the endocytic pathway, where peptide loading occurs. This step is mediated by a signal located in the cytoplasmic tail of the MHC class II-associated Ii chain, which directs the MHC class II-Ii complexes from the trans-Golgi network (TGN) to endosomes. The subcellular machinery responsible for the specific targeting of MHC class II molecules to the endocytic pathway, as well as the first compartments these molecules enter after exit from the TGN, remain unclear. We have designed an original experimental approach to selectively analyze this step of MHC class II transport. Newly synthesized MHC class II molecules were caused to accumulate in the Golgi apparatus and TGN by incubating the cells at 19°C, and early endosomes were functionally inactivated by in vivo cross-linking of transferrin (Tf) receptor–containing endosomes using Tf-HRP complexes and the HRP-insoluble substrate diaminobenzidine. Inactivation of Tf-containing endosomes caused a marked delay in Ii chain degradation, peptide loading, and MHC class II transport to the cell surface. Thus, early endosomes appear to be required for delivery of MHC class II molecules to the endocytic pathway. Under cross-linking conditions, most αβIi complexes accumulated in tubules and vesicles devoid of γ-adaptin and/or mannose-6-phosphate receptor, suggesting an AP1-independent pathway for the delivery of newly synthesized MHC class II molecules from the TGN to endosomes.

scholarly journals Accelerated Turnover of MHC Class II Molecules in Nonobese Diabetic Mice Is Developmentally and Environmentally Regulated In Vivo and Dispensable for Autoimmunity

2013 ◽  
Vol 190 (12) ◽  
pp. 5961-5971 ◽  
Author(s):  
Alessandra De Riva ◽  
Mark C. Varley ◽  
Leslie J. Bluck ◽  
Anne Cooke ◽  
Michael J. Deery ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Class Ii ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice ◽  
Mhc Class Ii Molecules
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