Major Histocompatibility Complex Class I: Difference between revisions
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==Major Histocompatibility Complex (MHC) Class I: Historical Background== | ==Major Histocompatibility Complex (MHC) Class I: Historical Background== | ||
''Major Histocompatibility Complex'' (MHC) refers to a complex of closely linked genes first identified in the early to mid-20th century as being the major factors in the rejection of living tissue allografts (grafts between members of the same species). It was these studies that gave MHC its name. Many other genes contribute to tissue allograft rejection to minor degrees, and these were called ''minor histocompatibility genes''. MHC genes code for MHC proteins that are the major antigens responsible for tissue allograft rejection. George D. Snell received one third of the [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/ 1980 Nobel Prize in Physiology or Medicine] for his contributions to the identification and characterization of these genes. Of course many other researchers made crucial contributions and they are credited in [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/snell-lecture.pdf Snell's Nobel Lecture]. Jean Dausset received a third of the [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/ 1980 Nobel Prize in Physiology or Medicine] for demonstrating the existence of MHC genes and proteins in humans, the latter being called ''Human Leukocyte Antigens'' ('''HLA'''). In mice, the most-used experimental model for studying MHC, the histocompatibility genetic loci were numbered H-1, H-2, H-3, and so forth. '''H-2''' is the major histocompatibility locus, while all the others are minor. Both HLA and H-2 turned out to be large complexes of closely-linked genes. | ''Major Histocompatibility Complex'' (MHC) refers to a complex of closely linked genes first identified in the early to mid-20th century as being the major factors in the rejection of living tissue allografts (grafts between members of the same species). It was these studies that gave MHC its name. Many other genes contribute to tissue allograft rejection to minor degrees, and these were called ''minor histocompatibility genes''. MHC genes code for MHC proteins that are the major antigens responsible for tissue allograft rejection. George D. Snell received one third of the [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/ 1980 Nobel Prize in Physiology or Medicine] for his contributions to the identification and characterization of these genes. Of course many other researchers made crucial contributions and they are credited in [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/snell-lecture.pdf Snell's Nobel Lecture]. Jean Dausset received a third of the [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/ 1980 Nobel Prize in Physiology or Medicine] for demonstrating the existence of MHC genes and proteins in humans, the latter being called ''Human Leukocyte Antigens'' ('''HLA'''). In mice, the most-used experimental model for studying MHC, the histocompatibility genetic loci were numbered H-1, H-2, H-3, and so forth. '''H-2''' is the major histocompatibility locus, while all the others are minor. Both HLA and H-2 turned out to be large complexes of closely-linked genes. | ||
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==3D Structure and Its Significance== | ==3D Structure and Its Significance== | ||
By the mid-1980's, there was abundant evidence that the ability of T lymphocytes to recognize antigen is "restricted" by MHC. However, what this "restriction" meant in terms of molecular mechanism was far from clear. Speculation about possible mechanisms raged for over a decade following Zinkernagel and Doherty's 1975 insight. But no experimental evidence available at the time was able to explain the "restriction". As an illustration, Figure 7 in [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/benacerraf-lecture.html Benacerraf's Nobel Lecture] shows his thinking in 1980. The figure shows an "Ia molecule" hypothetically "specifically interacting" with an "antigen fragment". Note that although the genetic linkage between Ia (the molecule coded for by immune response genes) and MHC was well established, it was not yet clear that Ia was MHC. Benacerraf's thinking was correct, as far as it went, but the details were not yet available. | By the mid-1980's, there was abundant evidence that the ability of T lymphocytes to recognize antigen is "restricted" by MHC. However, what this "restriction" meant in terms of molecular mechanism was far from clear. Speculation about possible mechanisms raged for over a decade following Zinkernagel and Doherty's 1975 insight. But no experimental evidence available at the time was able to explain the "restriction". As an illustration, Figure 7 in [http://nobelprize.org/nobel_prizes/medicine/laureates/1980/benacerraf-lecture.html Benacerraf's Nobel Lecture] shows his thinking in 1980. The figure shows an "Ia molecule" hypothetically "specifically interacting" with an "antigen fragment". Note that although the genetic linkage between Ia (the molecule coded for by immune response genes) and MHC was well established, it was not yet clear that Ia was MHC. Benacerraf's thinking was correct, as far as it went, but the details were not yet available. | ||
[[Image:1hla_edm_fig6b.jpg|right|thumb|340 px|<font color='blue'>Electron density of HLA-A2 peptide-binding groove</font> showing <font color='#ca4e61'>density of mixed peptides</font>. Figure 6b from [[1hla#Reference | Bjorkman <i>et al., Nature</i> <b>329</b>:506]], used with permission of Dr. Pamela Bjorkman.]] | |||
In 1987, Bjorkman and coworkers (in the laboratory of Don Wiley at Harvard) published the first empirical structure of MHC, a crystallographic structure of the human MHC Class I protein HLA-A2 ([[1hla]]). Although the resolution was low (3.5 Å), there was sufficient information to explain the decade-long mystery of how MHC restricts the recognition of foreign antigens by T lymphocytes. It is difficult to exaggerate the impact that this structure, and those that followed, had on the field of immunology. | In 1987, Bjorkman and coworkers (in the laboratory of Don Wiley at Harvard) published the first empirical structure of MHC, a crystallographic structure of the human MHC Class I protein HLA-A2 ([[1hla]]). Although the resolution was low (3.5 Å), there was sufficient information to explain the decade-long mystery of how MHC restricts the recognition of foreign antigens by T lymphocytes. It is difficult to exaggerate the impact that this structure, and those that followed, had on the field of immunology. | ||
Wiley's team struggled for many years to obtain sufficient MHC protein and high quality crystals. During this struggle, their funding ran out but they persevered, using funds from other projects (personal communication to [[User:Eric Martz |Eric Martz]] from Wiley, ca. 1989). The MHC protein was obtained from cultures of human cells (the JY B lymphocyte cell line) by a well-established but arduous process that earlier had been used for obtaining the amino acid sequences of HLA proteins by Strominger and coworkers. Papain was used to cleave the soluble extracellular domains of the HLA MHC proteins from their transmembrane domains, and the HLA-A2 domains were purified, separating them from HLA-B7 among many other proteins present on these cells. | Wiley's team struggled for many years to obtain sufficient MHC protein and high quality crystals. During this struggle, their funding ran out but they persevered, using funds from other projects (personal communication to [[User:Eric Martz |Eric Martz]] from Wiley, ca. 1989). The MHC protein was obtained from cultures of human cells (the JY B lymphocyte cell line) by a well-established but arduous process that earlier had been used for obtaining the amino acid sequences of HLA proteins by Strominger and coworkers. Papain was used to cleave the soluble extracellular domains of the HLA MHC proteins from their transmembrane domains, and the HLA-A2 domains were purified, separating them from HLA-B7 among many other proteins present on these cells. | ||
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==MHC Structure Tutorial== | ==MHC Structure Tutorial== | ||
A tutorial about the structure of MHC is available at [http://molviz.org MolviZ.Org]. It includes side by side comparisons of two different viral epitopes in MHC class I (with synchronized mouse rotation), of epitopes in MHC I vs. II, and a chapter on MHC class II structure. | A tutorial about the structure of MHC is available at [http://molviz.org MolviZ.Org]. It includes side by side comparisons of two different viral epitopes in MHC class I (with synchronized mouse rotation), of epitopes in MHC I vs. II, and a chapter on MHC class II structure. | ||
==Recognition of MHC I (HLA A2:01) by T Cell Receptor Mimetic Antibodies== | |||
A recent study called ''Targeting a neoantigen derived from a common TP53 mutation'' describes the means by which T Cell Receptor mimic (TCRm) antibodies were created a new class of immunotherapy. TP53, tumor protein 53, is a tumor suppressor gene, and is the most commonly mutated protein in cancers. Most [[P53]] is located inside the cell, the largest concentration is in the nucleus, which makes it difficult to find a treatment for TP53. Scientists have been struggling to design a drug to target this inactivated tumor suppressor gene. However, a small percentage is degraded by proteasomes and is present on the cell surface by MHC, Human Leukocyte Antigen (HLA). The most frequent mutation in the TP53 gene is a substitution from Arginine to Histidine at codon 175 (R175H). Most mutations within this gene occur as single-nucleotide variants at positions nearest to the DNA-binding domain. Using an HLA TP53 complex researchers discovered that neoantigen p53R175H is displayed by HLA:A2 on the cell surface at very low density. These peptide-HLA (pHLA) complexes are naturally ligands for T-cell receptors (TCRs). The advantage of using TCRm’s for immunotherapies is that they are easier to graft into different therapuetic formats and are an off the shelf ready to use therapy. Specifically, researchers developed a bispecific antibody constructed from H2 and an antiCD3 antibody, (H2- scDb) that can activate T cells even when the pHLA complex is expressed at very low, endogenous levels. This promising research shows that MHC I can be a key player in the fight against cancers caused by p53 mutations. <ref>DOI: 10.1126/science.abc8697</ref>. See below for interactive figures from this research. | |||
<html5media height="640" width="640">https://vimeo.com/540292892</html5media> | |||
The video above depicts the 3D structure of the pHLA (p53R175H/HLA-A*02:01) that is bound to an H2-Fab fragment (PDB 6W51). The Fab fragment is colored according to its heavy chains (dark blue) and light chains (cyan). The Fab fragment is bound to the C terminus of the pHLA complex, where HLA-A*02:01 is colored gray and the β2 microglobulin is colored in gold. Sandwiched in between alpha helices of HLA are nine amino acids that are part of p53R175H shown light green. | |||
<html5media height="640" width="640">https://vimeo.com/540291923</html5media> | |||
This video shows the same structure from above, but zooming in shows the interaction of the pHLA with complementarity-determining regions. Hydrogen bonds are shown as dashed lines. | |||
==MHC Structures== | ==MHC Structures== | ||
A list of MHC structures is at [[Major histocompatibility complex]]. | A list of MHC structures is at [[Major histocompatibility complex]]. | ||
==References== | |||
<references/> | |||
