The HLA System  

Jan Klein, Ph.D. and Akie Sato, Ph.D.

Volume 343(10):702-709, Sep 7, 2000

Volume 343(11):782-786, Sep14, 2000

Figure 1. Location and Organization of the HLA Complex on Chromosome 6.

The complex is conventionally divided into three regions: I, II, and III. Each region contains numerous loci (genes), only some of which are shown. Of the class I and II genes, only the expressed genes are depicted. Class III genes are not related to class I and class II genes structurally or functionally. BF denotes complement factor B; C2 complement component 2; C21B cytochrome P-450, subfamily XXI; C4A and C4B complement components 4A and 4B, respectively; HFE hemochromatosis; HSP heat-shock protein; LMP large multifunctional protease; LTA and LTB lymphotoxins A and B, respectively; MICA and MICB major-histocompatibility-complex class I chain genes A and B, respectively; P450 cytochrome P-450; PSMB8 and 9 proteasome ß 8 and 9, respectively; TAP1 and TAP2 transporter associated with antigen processing 1 and 2, respectively; TAPBP TAP-binding protein (tapasin); TNF-{alpha} tumor necrosis factor {alpha}; and HSPA1A, HSPA1B, and HSPA1L heat-shock protein 1A A-type, heat-shock protein 1A B-type, and heat-shock protein 1A–like, respectively.


Figure 2. Structure of HLA Class I and Class II Molecules.

Beta2-microglobulin (ß2m) is the light chain of the class I molecule. The α chain of the class I molecule has two peptide-binding domains (α1 and α2), an immunoglobulin-like domain (α3), the transmembrane region (TM), and the cytoplasmic tail. Each of the class II α and ß chains has four domains: the peptide-binding domain (α1 or ß1), the immunoglobulin-like domain ({alpha}2 or ß2), the transmembrane region, and the cytoplasmic tail.



Figure 3. Antigen Processing.

Panel A shows the principal pathways of generating peptides for loading onto HLA class I molecules. Worn-out or defective proteins in the cytosol are degraded into peptides in proteasomes. Selected peptides are then transported into the endoplasmic reticulum, where they are loaded onto newly synthesized class I molecules. The HLA–peptide complexes are exported by way of the Golgi apparatus to the surface of the cell. In tissues infected with a virus, viral particles are taken up by cells and uncoated. The viral DNA or RNA enters the nucleus and replicates within it. The viral messenger RNA (mRNA) then enters the cytosol and is transcribed into proteins. Some of the proteins are subsequently degraded in proteasomes, and the peptides are delivered into the endoplasmic reticulum, where they are loaded onto class I molecules for export to the surface of the cell. Panel B shows the processing of extracellular proteins. Self or foreign proteins are taken up by endocytosis (or phagocytosis) and sequestered into endosomes. Class II molecules synthesized in the endoplasmic reticulum are delivered by way of the Golgi apparatus into primary lysosomes, which fuse with the early endosomes to form the major-histocompatibility-complex (MHC) class II compartment. Enzymes brought into this compartment by the lysosomes degrade the engulfed proteins into peptides. HLA-DM molecules synthesized in the endoplasmic reticulum and delivered into the MHC class II compartment by transport vesicles help load the peptides onto the class II molecules. The HLA–peptide complexes are then exported to the surface of the cell.

Figure 4. Ribbon Model of the Tertiary Structure of an HLA Class I Peptide-Binding Module.

The model is shown from the top. The ß-pleated sheets are composed of the α {alpha} chain.





Figure 5. Interactions between HLA Molecules and Peptides.

Panel A shows examples of peptide motifs. The listed nonamers, as well as many others,7 have been found in complexes with the indicated HLA class I molecules. The anchor residues are highlighted in yellow. In Panel B, a longitudinal section through the peptide-binding groove of an HLA class I molecule, the side chains of amino acid residues composing the bound peptide (P1 through P9) are oriented either down into the pockets of the HLA molecule or up. The following amino acids are shown: alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y).

Figure 6. Interactions between a T-Cell Receptor and the HLA–Peptide Complex.

Panel A shows the diagonal orientation of the T-cell receptor on the surface of the HLA–peptide complex. Panel B shows the bridge between a T cell and the antigen-presenting cell created by the interaction between the T-cell receptor and the HLA–peptide complex. Complementarity-determining region 1 of the {alpha} and ß chains of the T-cell receptor is not visible in this depiction because one is positioned behind and the other in front of the part shown. Beta2-microglobulin (ß2m) is the light chain of the class I molecule. The three complementarity-determining regions (CDR1, CDR2, and CDR3) are shown.



[정리:  2001.07.16]