page_title: History and naming of human leukocyte antigens
section_title: MHC restriction
hierarchical_section_title: History and naming of human leukocyte antigens / Discovery / MHC restriction
caption_attribution_description: English: This is the protein structure of HLA-A*02 as determined by Madura, F. et. al. in T-cell receptor specificity maintained by altered thermodynamics in 2013 in the Journal of Biological Chemistry.
context_page_description: Human leukocyte antigens began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences.
  An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.
context_section_description: Late in 1973 a pair of researchers in Australia, Rolf Zinkernagel and Peter Doherty made a revelatory discovery that altered the thinking of immunologists forever. The pair was doing research on viral infections in mice and noticed that T-cells that prevented viral infections in some mice wouldn't always prevent the same infection in other mice. After looking at the MHCs present in the mice, they realized that cytotoxic T-cells could only identify virus infections in cells with the right Class I compatibility gene. Traditional thinking was that the immune system identified infections directly but this discovery turned that theory on its head. Compatibility genes were essential in immune system mediated viral clearing. The pair coined the term "MHC Restriction" to describe this relationship between T-cells, specific MHC proteins, and viral detection. In 1975, in an article in the journal Lancet, they introduced the idea of "altered self", meaning that viruses alter the MHC proteins and this alteration is detected by T-cells. For their work they won the 1996 Nobel Prize. It took the work of many others to determine how T-cells made this identification.
caption: The structure of the HLA-A*02 protein. The spirals (α-helices) at the top of the image are the edges of the binding groove. The red line between them signifies a peptide (in this case an E1A heteroclitic variant of melanoma peptide). The arrows (β-sheets) serve as the anchor that holds the protein in the cell membrane.[7]
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