scholarly journals Experimental evidence for major histocompatibility complex–allele–specific resistance to a bacterial infection

2002 ◽  
Vol 269 (1504) ◽  
pp. 2029-2033 ◽  
Author(s):  
Jakob Lohm ◽  
Mats Grahn ◽  
Åsa Langefors ◽  
Øivind Andersen ◽  
Arne Storset ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Bacterial Infection ◽  
Experimental Evidence ◽  
Specific Resistance ◽  
Major Histocompatibility Complex Allele ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Allele Specific

scholarly journals Supermotifs enable natural invariant chain-derived peptides to interact with many major histocompatibility complex-class II molecules.

1995 ◽  
Vol 181 (2) ◽  
pp. 527-536 ◽  
Author(s):  
G Malcherek ◽  
V Gnau ◽  
G Jung ◽  
H G Rammensee ◽  
A Melms
Keyword(s):  
Major Histocompatibility Complex ◽  
Class Ii ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Contact Site ◽  
Contact Sites ◽  
Histocompatibility Complex ◽  
Natural Ligands ◽  
Specific Contact ◽  
Allele Specific

Class II-associated invariant chain peptides (CLIPs) compete with natural allele-specific ligands for binding to several purified HLA-DR molecules. Truncation and substitution analysis showed that a minimal sequence of 13 amino acids is sufficient for excellent binding to DR17 and DR1. Hydrophobic residues at relative positions 1 and 9 (P1 and P9) which are shared among these DR-ligands, and are found to be anchored in complementary pockets by x-ray crystallography allow specific binding. Two flanking residues at either end next to the specific contact sites Met107 and Met115 contribute to binding irrespective of their side chains, suggesting H-bonds to the major histocompatibility complex (MHC) molecule. Thus, CLIPs behave like conventional ligands, however, lack their allele-specific contact sites. Introduction of the DR17-specific contact site aspartate at P4 dramatically improves invariant chain-peptide binding to DR17, but reduces DR1 binding. By contrast, binding to DR1, but not DR17 is strongly improved after introduction of the DR1-specific contact site alanine at P6. In addition, analyzing the fine specificity of the hydrophobic contact sites at P1 and P9, CLIP variants reflected the allele-specific preferences of DR17- or DR1-ligands, respectively, for aliphatic or aromatic residues. Alignment studies suggest that CLIPs are designed for promiscuous binding in the groove of many MHC class II molecules by taking advantage of one or more supermotifs. One such supermotif, for example, does not include the DR17-specific contact site aspartate at P4, which in conventional natural ligands like Apolipoprotein (2877-94) is necessary to confer a stable conformation. Introduction of aspartate at P4 generates a CLIP variant that is stable in the presence of sodium dodecyl sulfate, such as allele-specific ligands. Studying the stability of class II-CLIP complexes at pH 5, we found that CLIPs, similar to anchor-amputated ligands, can be released from class II molecules, in contrast to conventional natural ligands, which were irreversibly bound. Taken together, our data provide compelling evidence that CLIP peptides bind into the class II groove.

scholarly journals Major Histocompatibility Complex Class I Allele-specific Cooperative and Competitive Interactions between Immune Evasion Proteins of Cytomegalovirus

2002 ◽  
Vol 196 (6) ◽  
pp. 805-816 ◽  
Author(s):  
Markus Wagner ◽  
Anja Gutermann ◽  
Jürgen Podlech ◽  
Matthias J. Reddehase ◽  
Ulrich H. Koszinowski
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Surface Expression ◽  
Inhibitory Effect ◽  
Class I ◽  
Major Influence ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Allele Specific ◽  
Infected Cells

Cytomegaloviruses (CMVs) deploy a set of genes for interference with antigen presentation in the major histocompatibility complex (MHC) class I pathway. In murine CMV (MCMV), three genes were identified so far: m04/gp34, m06/gp48, and m152/gp40. While their function as immunoevasins was originally defined after their selective expression, this may not necessarily reflect their biological role during infection. The three immunoevasins might act synergistically, but they might also compete for their common substrate, the MHC class I complexes. To approach this question in a systematic manner, we have generated a complete set of mutant viruses with deletions of the three genes in all seven possible combinations. Surface expression of a set of MHC class I molecules specified by haplotypes H-2d (Kd, Dd, and Ld) and H-2b (Kb and Db) was the parameter for evaluation of the interference with class I trafficking. The data show the following: first, there exists no additional MCMV gene of major influence on MHC class I surface expression; second, the strength of the inhibitory effect of immunoevasins shows an allele-specific hierarchy; and third, the immunoevasins act not only synergistically but can, in certain combinations, interact antagonistically. In essence, this work highlights the importance of studying the immunosubversive mechanisms of cytomegaloviruses in the context of gene expression during the viral replicative cycle in infected cells.

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