Nonclassical behavior of the thymus leukemia antigen: peptide transporter-independent expression of a nonclassical class I molecule.

The thymus leukemia (TL) antigen is a major histocompatibility complex-encoded nonclassical class I molecule. Here we present data demonstrating that expression of the TL antigen, unlike other class I molecules, is completely independent of the function of the transporter associated with antigen processing (TAP). The TL antigen is expressed by transfected TAP-2-deficient RMA-S cells when these cells are grown at 37 degrees C. In transfected RMA cells, the kinetics of arrival of TL antigen on the cell surface are similar to those of a classical class I molecule. The kinetics are not altered in TAP-deficient RMA-S cells, demonstrating that surface TL expression in TAP-deficient cells is not due to the stable expression of a few molecules that leak out by a TAP-independent pathway. Soluble TL molecules produced by Drosophila melanogaster cells are highly resistant to thermal denaturation, unlike peptide-free classical class I molecules synthesized by these insect cells. In addition, these soluble TL molecules are devoid of detectable bound peptides. The results demonstrate that the TL antigen is capable of reaching the surface without bound peptide, although acquisition of peptide or some other ligand through a TAP-independent pathway cannot be formally excluded. We speculate that the ability of the TL antigen to reach the cell surface, under conditions in which other class I molecules do not, may be related to a specialized function of the TL molecule in the mucosal immune system, and possibly in the stimulation of intestinal gamma delta T cells.

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From Chickens to Humans: The Importance of Peptide Repertoires for MHC Class I Alleles

Frontiers in Immunology ◽

10.3389/fimmu.2020.601089 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jim Kaufman

Keyword(s):

Cell Surface ◽

Cell Function ◽

Nk Cell ◽

Class I ◽

Ligand Interaction ◽

Mhc I ◽

Peptide Motifs ◽

Classical Class ◽

Histocompatibility Complex ◽

High Level

In humans, killer immunoglobulin-like receptors (KIRs), expressed on natural killer (NK) and thymus-derived (T) cells, and their ligands, primarily the classical class I molecules of the major histocompatibility complex (MHC) expressed on nearly all cells, are both polymorphic. The variation of this receptor-ligand interaction, based on which alleles have been inherited, is known to play crucial roles in resistance to infectious disease, autoimmunity, and reproduction in humans. However, not all the variation in response is inherited, since KIR binding can be affected by a portion of the peptide bound to the class I molecules, with the particular peptide presented affecting the NK response. The extent to which the large multigene family of chicken immunoglobulin-like receptors (ChIRs) is involved in functions similar to KIRs is suspected but not proven. However, much is understood about the two MHC-I molecules encoded in the chicken MHC. The BF2 molecule is expressed at a high level and is thought to be the predominant ligand of cytotoxic T lymphocytes (CTLs), while the BF1 molecule is expressed at a much lower level if at all and is thought to be primarily a ligand for NK cells. Recently, a hierarchy of BF2 alleles with a suite of correlated properties has been defined, from those expressed at a high level on the cell surface but with a narrow range of bound peptides to those expressed at a lower level on the cell surface but with a very wide repertoire of bound peptides. Interestingly, there is a similar hierarchy for human class I alleles, although the hierarchy is not as wide. It is a question whether KIRs and ChIRs recognize class I molecules with bound peptide in a similar way, and whether fastidious to promiscuous hierarchy of class I molecules affect both T and NK cell function. Such effects might be different from those predicted by the similarities of peptide-binding based on peptide motifs, as enshrined in the idea of supertypes. Since the size of peptide repertoire can be very different for alleles with similar peptide motifs from the same supertype, the relative importance of these two properties may be testable.

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Crystal structures of lysophospholipid-bound MHC class I molecules

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011932 ◽

2020 ◽

Vol 295 (20) ◽

pp. 6983-6991 ◽

Cited By ~ 1

Author(s):

Yoko Shima ◽

Daisuke Morita ◽

Tatsuaki Mizutani ◽

Naoki Mori ◽

Bunzo Mikami ◽

...

Keyword(s):

Cell Surface ◽

Crystal Structures ◽

Mhc Class I ◽

Antigen Processing ◽

Surface Expression ◽

Class I ◽

Cell Surface Expression ◽

Peptide Antigens ◽

Histocompatibility Complex ◽

Mhc Class I Molecules

Newly synthesized major histocompatibility complex (MHC) class I proteins are stabilized in the endoplasmic reticulum (ER) by binding 8–10-mer-long self-peptide antigens that are provided by transporter associated with antigen processing (TAP). These MHC class I:peptide complexes then exit the ER and reach the plasma membrane, serving to sustain the steady-state MHC class I expression on the cell surface. A novel subset of MHC class I molecules that preferentially bind lipid-containing ligands rather than conventional peptides was recently identified. The primate classical MHC class I allomorphs, Mamu-B*098 and Mamu-B*05104, are capable of binding the N-myristoylated 5-mer (C14-Gly-Gly-Ala-Ile-Ser) or 4-mer (C14-Gly-Gly-Ala-Ile) lipopeptides derived from the N-myristoylated SIV Nef protein, respectively, and of activating lipopeptide antigen-specific cytotoxic T lymphocytes. We herein demonstrate that Mamu-B*098 samples lysophosphatidylethanolamine and lysophosphatidylcholine containing up to a C20 fatty acid in the ER. The X-ray crystal structures of Mamu-B*098 and Mamu-B*05104 complexed with lysophospholipids at high resolution revealed that the B and D pockets in the antigen-binding grooves of these MHC class I molecules accommodate these lipids through a monoacylglycerol moiety. Consistent with the capacity to bind cellular lipid ligands, these two MHC class I molecules did not require TAP function for cell-surface expression. Collectively, these results indicate that peptide- and lipopeptide-presenting MHC class I subsets use distinct sources of endogenous ligands.

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Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

Journal of Virology ◽

10.1128/jvi.75.21.10557-10562.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10557-10562 ◽

Cited By ~ 48

Author(s):

Sayeh Vahdati Ben-Arieh ◽

Baruch Zimerman ◽

Nechama I. Smorodinsky ◽

Margalit Yaacubovicz ◽

Chana Schechter ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Human Cytomegalovirus ◽

Viral Protein ◽

Complex Molecule ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Classical Class ◽

Histocompatibility Complex ◽

Nonclassical Class

ABSTRACT HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/β2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.

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Ancient interlocus exon exchange in the history of the HLA-A locus.

Genetics ◽

10.1093/genetics/122.3.681 ◽

1989 ◽

Vol 122 (3) ◽

pp. 681-686 ◽

Cited By ~ 1

Author(s):

A L Hughes ◽

M Nei

Keyword(s):

Major Histocompatibility Complex ◽

Present Finding ◽

Evolutionary Process ◽

Class I ◽

Hybrid Gene ◽

Classical Class ◽

Histocompatibility Complex ◽

History Of ◽

Mhc Polymorphism ◽

Nonclassical Class

Abstract The major histocompatibility complex (MHC) in humans and chimpanzees includes three classical class I loci, A, B and C, which encode glycoproteins expressed on the surface of all nucleated cells. There are also several nonclassical class I loci including E, which have more limited expression. By analyzing published sequences, we have shown that in exons 4 and 5, A locus alleles from both humans and chimpanzees are much more similar to E than to B or C alleles, whereas in exons 2 and 3 alleles from all three classical class I loci are much more similar to each other than any one is to E. We propose that some 20 million years ago, interlocus recombination led to the formation of a hybrid gene in which exons 2 and 3 were derived from the original A locus and exons 4 and 5 were derived from the E locus. The fact that such an ancient event can still be detected suggests that interlocus recombination is rare in the MHC and does not significantly contribute to MHC polymorphism, which is known to be extremely high. The present finding, however, supports Gilbert's idea that exons in a gene may occasionally be replaced by those from another gene in the evolutionary process.

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Fcγ Receptor–mediated Induction of Dendritic Cell Maturation and Major Histocompatibility Complex Class I–restricted Antigen Presentation after Immune Complex Internalization

Journal of Experimental Medicine ◽

10.1084/jem.189.2.371 ◽

1999 ◽

Vol 189 (2) ◽

pp. 371-380 ◽

Cited By ~ 665

Author(s):

Armelle Regnault ◽

Danielle Lankar ◽

Valérie Lacabanne ◽

Ana Rodriguez ◽

Clotilde Théry ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Antigen Presentation ◽

Mhc Class I ◽

Mhc Class Ii ◽

Antigen Processing ◽

Class I ◽

Peptide Transporter ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Dc Maturation

Dendritic cells (DCs) express several receptors for the Fc portion of immunoglobulin (Ig)G (FcγR), which mediate internalization of antigen–IgG complexes (immune complexes, ICs) and promote efficient major histocompatibility complex (MHC) class II–restricted antigen presentation. We now show that FcγRs have two additional specific attributes in murine DCs: the induction of DC maturation and the promotion of efficient MHC class I–restricted presentation of peptides from exogenous, IgG-complexed antigens. Both FcγR functions require the FcγR-associated γ chain. FcγR-mediated MHC class I–restricted antigen presentation is extremely sensitive and specific to immature DCs. It requires proteasomal degradation and is dependent on functional peptide transporter associated with antigen processing, TAP1-TAP2. By promoting DC maturation and presentation on both MHC class I and II molecules, ICs should efficiently sensitize DCs for priming of both CD4+ helper and CD8+ cytotoxic T lymphocytes in vivo.

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Trimming of antigenic peptides in an early secretory compartment.

Journal of Experimental Medicine ◽

10.1084/jem.180.6.2389 ◽

1994 ◽

Vol 180 (6) ◽

pp. 2389-2394 ◽

Cited By ~ 135

Author(s):

H L Snyder ◽

J W Yewdell ◽

J R Bennink

Keyword(s):

Mhc Class I ◽

Antigen Processing ◽

Secretory Pathway ◽

Signal Sequence ◽

Class I ◽

Peptide Transporter ◽

Optimal Size ◽

Antigenic Peptides ◽

Histocompatibility Complex ◽

Proteolytic Activities

Major histocompatibility complex (MHC) class I molecules bind peptides of 8-10 residues in the endoplasmic reticulum (ER) and convey them to the cell surface for inspection by CD8-expressing T cells (TCD8+). Antigenic peptides are predominantly derived from a cytosolic pool of polypeptides. The proteolytic generation of peptides from polypeptides clearly begins in the cytosol, but it is uncertain whether the final proteolytic steps occur before or after peptides are transported into the ER by the MHC-encoded peptide transporter (TAP). To study the trimming of antigenic peptides in the secretory pathway in the absence of cytosolic processing, we used an NH2-terminal signal sequence to target to the ER of TAP-deficient cells, "tandem" peptides consisting of two defined TCD8+ determinants arranged from head to tail. We find that in contrast to cytosolic proteases in TAP-expressing cells, which are able to liberate antigenic peptides from either end of a tandem peptide, proteases (probably aminopeptidases) present in an early secretory compartment preferentially liberate the COOH-terminal determinant. These findings demonstrate that proteolytic activities associated with antigen processing are not limited to the cytosol, but that they also exist in an early secretory compartment. Such secretory aminopeptidases may function to trim TAP-transported peptides to the optimal size for binding to class I molecules.

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Ligand Design for Specific MHC Class I Molecules on the Cell Surface

10.26434/chemrxiv.12865688 ◽

2020 ◽

Author(s):

Xizheng Sun ◽

Reika Tokunaga ◽

Yoko Nagai ◽

Ryo Miyahara ◽

Akihiro Kishimura ◽

...

Keyword(s):

Cell Surface ◽

Mhc Class I ◽

Targeted Delivery ◽

Peptide Ligands ◽

Class I ◽

Class I Mhc ◽

Mhc I ◽

Histocompatibility Complex ◽

High Binding Affinity ◽

Mhc Class I Molecules

<p><a></a><a></a><a>We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I)</a> molecules on cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to the MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. The present strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed autoimmune diseases.</p>

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