Major histocompatibility complex (MHC) class I and class II proteins: impact of polymorphism on antigen presentation

We have previously described a set of mutants (16.23-selected mutants) of a B lymphoblastoid cell line that are defective in the presentation of intact proteins to class II-restricted T cells, but effectively present immunogenic peptides. The mutations in these mutants are recessive in somatic cell hybrids and are not in Class II structural genes. Here, we report on a unique mutant, 5.2.4, in which a similar defect in class II-restricted antigen presentation has occurred in association with a one-megabase homozygous deletion in the class II region of the major histocompatibility complex (MHC). The defects in class II presentation among three of the 16.23-selected mutants, and between these mutants and 5.2.4, are noncomplementary in somatic cell hybrids. This suggests that the class II presentation-defective phenotype in all four mutants results from lesions in a single MHC-linked gene, a conclusion strengthened by the finding that in a hybrid made with a second, unrelated MHC deletion mutant, T2, the class II presentation defect in a 16.23-selected mutant is also not complemented. Mutant 5.2.4, in addition to its class II presentation defect, is also defective in surface expression of MHC class I molecules, most likely because its deletion encompasses the peptide supply factor 1 gene, whose function is known to be required for normal abundance of cell surface class I molecules. However, the surface abundance of class I molecules is normal in the 16.23-selected mutants, suggesting that the lesions affecting class I surface abundance and class II presentation result from mutations in different genes.

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Major histocompatibility complex (MHC) fragment numbers alone – in Atlantic cod and in general - do not represent functional variability

F1000Research ◽

10.12688/f1000research.15386.1 ◽

2018 ◽

Vol 7 ◽

pp. 963 ◽

Cited By ~ 2

Author(s):

Johannes M. Dijkstra ◽

Unni Grimholt

Keyword(s):

Major Histocompatibility Complex ◽

Mhc Class I ◽

Mhc Class Ii ◽

Fish Species ◽

Teleost Fish ◽

Class Ii ◽

Class I ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Speciation Rates

This correspondence concerns a publication by Malmstrøm et al. in Nature Genetics in October 2016. Malmstrøm et al. made an important contribution to fish phylogeny research by using low-coverage genome sequencing for comparison of 66 teleost (modern bony) fish species, with 64 of those 66 belonging to the species-rich clade Neoteleostei, and with 27 of those 64 belonging to the order Gadiformes. For these 66 species, Malmstrøm et al. estimated numbers of genes belonging to the major histocompatibility complex (MHC) class I lineages U and Z and concluded that in teleost fish these combined numbers are positively associated with, and a driving factor of, the rates of establishment of new fish species (speciation rates). They also claimed that functional genes for the MHC class II system molecules MHC IIA, MHC IIB, CD4 and CD74 were lost in early Gadiformes. Our main criticisms are (1) that the authors did not provide sufficient evidence for presence or absence of intact functional MHC class I or MHC class II system genes, (2) that they did not discuss that an MHC subpopulation gene number alone is a very incomplete measure of MHC variance, and (3) that the MHC system is more likely to reduce speciation rates than to enhance them. We conclude that their new model of MHC class I evolution, reflected in their title “Evolution of the immune system influences speciation rates in teleost fish”, is unsubstantiated. In addition, we explain that their “pinpointing” of the functional loss of the MHC class II system and all the important MHC class II system genes to the onset of Gadiformes is preliminary, because they did not sufficiently investigate the species at the clade border.

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Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

Infection and Immunity ◽

10.1128/iai.01254-15 ◽

2015 ◽

Vol 84 (2) ◽

pp. 480-490 ◽

Cited By ~ 6

Author(s):

Erik D. Cram ◽

Ryan S. Simmons ◽

Amy L. Palmer ◽

William H. Hildebrand ◽

Daniel D. Rockey ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Antigen Presentation ◽

Mhc Class I ◽

Class I ◽

Major Histocompatibility ◽

Content Type ◽

Histocompatibility Complex ◽

Peptide Presentation ◽

Mhc Class I Antigen ◽

Self Antigen

The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8+cytotoxic T lymphocytes.Chlamydiaspp. are obligate intracellular bacteria and, as such, should be targeted by CD8+T cells. It is likely thatChlamydiaspp. have evolved mechanisms to avoid the CD8+killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of variousChlamydiaspecies to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted todefectiveribosomalproducts, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest thatChlamydiaspp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins.

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Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment.

Journal of Experimental Medicine ◽

10.1084/jem.176.3.729 ◽

1992 ◽

Vol 176 (3) ◽

pp. 729-738 ◽

Cited By ~ 144

Author(s):

M del Val ◽

H Hengel ◽

H Häcker ◽

U Hartlaub ◽

T Ruppert ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Antigen Presentation ◽

Mhc Class I ◽

Heavy Chain ◽

Class I ◽

Antigenic Peptides ◽

Major Histocompatibility ◽

Early Genes ◽

Histocompatibility Complex ◽

Golgi Compartment

Selective expression of murine cytomegalovirus (MCMV) immediate-early (IE) genes leads to the presentation by the major histocompatibility complex (MHC) class I molecule Ld of a peptide derived from MCMV IE protein pp89 (Reddehase, M.J., J. B. Rothbard, and U.H. Koszinowski. 1989. Nature (Lond.). 337:651). Characterization of endogenous antigenic peptides identified the pp89 peptide as the nonapeptide 168YPHFMPTNL176 (del Val, M., H.-J. Schlicht, T. Ruppert, M.J. Reddehase, and U.H. Koszinowski. 1991. Cell. 66:1145). Subsequent expression of MCMV early genes prevents presentation of pp89 (del Val, M., K. Münch, M.J. Reddehase, and U.H. Koszinowski. 1989. Cell. 58:305). We report on the mechanism by which MCMV early genes interfere with antigen presentation. Expression of the IE promoter-driven bacterial gene lacZ by recombinant MCMV subjected antigen presentation of beta-galactosidase to the same control and excluded antigen specificity. The Ld-dependent presence of naturally processed antigenic peptides also in nonpresenting cells located the inhibitory function subsequent to the step of antigen processing. The finding that during the E phase of MCMV gene expression the MHC class I heavy chain glycosylation remained in an Endo H-sensitive form suggested a block within the endoplasmic reticulum/cis-Golgi compartment. The failure to present antigenic peptides was explained by a general retention of nascent assembled trimolecular MHC class I complexes. Accordingly, at later stages of infection a significant decrease of surface MHC class I expression was seen, whereas other membrane glycoproteins remained unaffected. Thus, MCMV E genes endow this virus with an effective immune evasion potential. These results also indicate that the formation of the trimolecular complex of MHC class I heavy chain, beta 2-microglobulin, and the finally trimmed peptide is completed before entering the medial-Golgi compartment.

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Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control

F1000Research ◽

10.12688/f1000research.10474.1 ◽

2017 ◽

Vol 6 ◽

pp. 158 ◽

Cited By ~ 22

Author(s):

Andy van Hateren ◽

Alistair Bailey ◽

Tim Elliott

Keyword(s):

Quality Control ◽

Major Histocompatibility Complex ◽

Antigen Presentation ◽

Mhc Class I ◽

Class I ◽

Major Histocompatibility ◽

Mhc I ◽

Histocompatibility Complex ◽

Peptide Loading ◽

Mhc Class I Molecules

We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells. Recognition by these sentinels of the immune system can lead to the destruction of the presenting cell, thus protecting the host from pathogens and cancer. Classical MHC class I molecules (MHC I hereafter) are co-dominantly expressed, polygenic, and exceptionally polymorphic and have significant sequence diversity. Thus, in most species, there are many different MHC I allotypes expressed, each with different peptide-binding specificity, which can have a dramatic effect on disease outcome. Although MHC allotypes vary in their primary sequence, they share common tertiary and quaternary structures. Here, we review the evidence that, despite this commonality, polymorphic amino acid differences between allotypes alter the ability of MHC I molecules to change shape (that is, their conformational plasticity). We discuss how the peptide loading co-factor tapasin might modify this plasticity to augment peptide loading. Lastly, we consider recent findings concerning the functions of the non-classical MHC I molecule HLA-E as well as the tapasin-related protein TAPBPR (transporter associated with antigen presentation binding protein-related), which has been shown to act as a second quality-control stage in MHC I antigen presentation.

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The requirement for proteasome activity class I major histocompatibility complex antigen presentation is dictated by the length of preprocessed antigen.

Journal of Experimental Medicine ◽

10.1084/jem.183.4.1545 ◽

1996 ◽

Vol 183 (4) ◽

pp. 1545-1552 ◽

Cited By ~ 27

Author(s):

B Yang ◽

Y S Hahn ◽

C S Hahn ◽

T J Braciale

Keyword(s):

Amino Acids ◽

Major Histocompatibility Complex ◽

Antigen Presentation ◽

Mhc Class I ◽

Proteasome Activity ◽

Class I ◽

Target Cells ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Mhc Class I Molecules

Accumulating evidence has implicated the proteasome in the processing of protein along the major histocompatibility complex (MHC) class I presentation pathway. The availability of potent proteasome inhibitors provides an opportunity to examine the role of proteasome function in antigen presentation by MHC class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). We have investigated the processing and presenting of antigenic epitopes from influenza hemagglutinin in target cells treated with the inhibitor of proteasome activity MG132. In the absence of proteasome activity, the processing and presentation of the full-length hemagglutinin was abolished, suggesting the requirement for proteasome function in the processing and presentation of the hemagglutinin glycoprotein. Epitope-containing translation products as short as 21 amino acids when expressed in target cells required proteasome activity for processing and presentation of the hemagglutin epitope to CTLs. However, when endogenous peptides of 17 amino acids or shorter were expressed in target cells, the processing and presentation of epitopes contained in these peptides were insensitive to the proteasome inhibitor. Our results support the hypothesis that proteasome activity is required for the generation of peptides presented by MHC class I molecules and that the requirement for proteasome activity is dependent on the size of the translation product expressed in the target cell. The implications of these findings are discussed.

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A third broad lineage of major histocompatibility complex (MHC) class I in teleost fish; MHC class II linkage and processed genes

Immunogenetics ◽

10.1007/s00251-007-0198-6 ◽

2007 ◽

Vol 59 (4) ◽

pp. 305-321 ◽

Cited By ~ 36

Author(s):

Johannes Martinus Dijkstra ◽

Takayuki Katagiri ◽

Kazuyoshi Hosomichi ◽

Kazuyo Yanagiya ◽

Hidetoshi Inoko ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Mhc Class I ◽

Mhc Class Ii ◽

Teleost Fish ◽

Class Ii ◽

Class I ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Processed Genes

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Specific suppression of major histocompatibility complex class I and class II genes in astrocytes by brain-enriched gangliosides.

Journal of Experimental Medicine ◽

10.1084/jem.178.4.1357 ◽

1993 ◽

Vol 178 (4) ◽

pp. 1357-1363 ◽

Cited By ~ 35

Author(s):

P T Massa

Keyword(s):

Major Histocompatibility Complex ◽

Mhc Class I ◽

Class Ii ◽

Binding Activity ◽

Inducible Expression ◽

Class I ◽

Mrna Levels ◽

Major Histocompatibility ◽

Ifn Gamma ◽

Histocompatibility Complex

The effect of brain-enriched gangliosides on constitutive and cytokine-inducible expression of major histocompatibility complex (MHC) class I and II genes in cultured astrocytes was studied. Before treatment with gangliosides, astrocytes expressed constitutive MHC class I but not class II molecules, however, the expression of both MHC class I and II cell surface molecules on astrocytes was induced to high levels by interferon gamma (IFN-gamma). Constitutive and IFN-gamma-inducible expression of MHC class I and II molecules was suppressed by treatment of astrocytes with exogenous bovine brain gangliosides in a dose-dependent manner. Constitutive and induced MHC class I and II mRNA levels were also suppressed by gangliosides, indicating control through transcriptional mechanisms. This was consistent with the ability of gangliosides to suppress the binding activity of transcription factors, especially NF-kappa B-like binding activity, important for the expression of both MHC class I and II genes. These studies may be important for understanding mechanisms of central nervous system (CNS)-specific regulation of major histocompatibility molecules in neuroectodermal cells and the role of gangliosides in regulating MHC-restricted antiviral and autoimmune responses within the CNS.

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Major histocompatibility complex (MHC) fragment numbers alone – in Atlantic cod and in general - do not represent functional variability

F1000Research ◽

10.12688/f1000research.15386.2 ◽

2018 ◽

Vol 7 ◽

pp. 963

Author(s):

Johannes M. Dijkstra ◽

Unni Grimholt

Keyword(s):

Major Histocompatibility Complex ◽

Mhc Class I ◽

Mhc Class Ii ◽

Fish Species ◽

Teleost Fish ◽

Class Ii ◽

Class I ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Speciation Rates

This correspondence concerns a publication by Malmstrøm et al. in Nature Genetics in October 2016. Malmstrøm et al. made an important contribution to fish phylogeny research by using low-coverage genome sequencing for comparison of 66 teleost (modern bony) fish species, with 64 of those 66 belonging to the species-rich clade Neoteleostei, and with 27 of those 64 belonging to the order Gadiformes. For these 66 species, Malmstrøm et al. estimated numbers of genes belonging to the major histocompatibility complex (MHC) class I lineages U and Z and concluded that in teleost fish these combined numbers are positively associated with, and a driving factor of, the rates of establishment of new fish species (speciation rates). They also claimed that functional genes for the MHC class II system molecules MHC IIA, MHC IIB, CD4 and CD74 were lost in early Gadiformes. Our main criticisms are (1) that the authors did not provide sufficient evidence for presence or absence of intact functional MHC class I or MHC class II system genes, (2) that they did not discuss that an MHC subpopulation gene number alone is a very incomplete measure of MHC variance, and (3) that the MHC system is more likely to reduce speciation rates than to enhance them. Furthermore, their use of the Ornstein-Uhlenbeck model is a typical example of overly naïve use of that model system. In short, we conclude that their new model of MHC class I evolution, reflected in their title “Evolution of the immune system influences speciation rates in teleost fish”, is unsubstantiated, and that their “pinpointing” of the functional loss of the MHC class II system and all the important MHC class II system genes to the onset of Gadiformes is preliminary, because they did not sufficiently investigate the species at the clade border.

Download Full-text