Major Histocompatibility Complex Class I
Major Histocompatibility Complex (MHC) genes, and the proteins they specify, play centrally important roles in adaptive immune responses. Each MHC protein molecule contains a groove that is loaded with a peptide fragment derived from an intracellular protein. The MHC proteins carry these peptides to the outer surface of the cell, where thymus-derived ("T") lymphocytes examine them. When the peptides are deemed to be foreign by the T lymphocytes, appropriate immune defenses are activated. T lymphocytes are centrally important in all adaptive immune responses, including antibody production and the elimination of intracellular parasites, and their responses depend entirely on the presentation of peptides by MHC. Class I MHC proteins, in particular, reveal the presence of otherwise hidden intracellular parasites (such as viruses and some bacteria) by displaying peptide fragments of parasite proteins on the cell surface. For more detail, please see Wikipedia: Major Histocompatibility Complex.
The 3D structure of MHC proteins was one of the highest impact crystallographic strucures of all time. In order to appreciate why, some historical background is helpful.
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 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 Snell's Nobel Lecture. Jean Dausset received a third of the 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.
Independently, in the early 1960's, Baruj Benacerraf and coworkers demonstrated the existence of immune response genes (Ir genes) that controlled the ability of an individual guinea pig's immune system to respond to simple synthetic amino acid polymers. Benacerraf was awarded one third of the 1980 Nobel Prize in Physiology or Medicine for discovering immune response genes. In the late 1960's, McDevitt and others found that the Ir genes were linked to MHC (for details, see Benacerraf's Nobel Lecture).
In 1975, Zinkernagel and Doherty made the surprising discovery that the ability of virus-specific T lymphocytes to recognize virus infection, in virus-infected cells, depended upon the MHC genotype of the infected cells. The MHC had to match that present when the T lymphocytes were first activated by the virus. This "restriction" of antigen recognition by T cells was confirmed in many other systems. In 1996, Zinkernagel and Doherty were awarded the Nobel Prize in Physiology or Medicine for this discovery. By that time, the mechanism of the "restriction" they had observed was clear -- thanks to the 3D structure of MHC Class I.
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 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.
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 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.
Because the protein was obtained from living cells, its peptide-accomodating groove (blue in figure at right) contained a mixture of unknown peptides (salmon-colored in figure at right). These appeared in the crystal structure of 1hla as an electron density that could not be explained by the known sequence of HLA-A2, lying within a groove the alpha chain of that molecule, in their Fig. 6b (at right). This phenomenally enlightening preview of ghostly peptides being presented to T cells by MHC gave goosebumps to cellular immunologists of the time.
(to be continued)
MHC Structure Tutorial
A tutorial about the structure of MHC is available at 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 list of MHC structures is at Major histocompatibility complex.