Major Histocompatibility Complex Class I: Difference between revisions
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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 fundamentally important finding meant in terms of molecular mechanism was far from clear. Speculation about possible mechanisms raged for over a decade following Zinkernagel and Doherty's 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 fundamentally important finding meant in terms of molecular mechanism was far from clear. Speculation about possible mechanisms raged for over a decade following Zinkernagel and Doherty's 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. | ||
In 1987, Bjorkman and coworkers ... | 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 this structure 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 by using funds from other projects (personal communication to [[Emartz]] from Wiley in 1988). 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. | |||
(to be continued) | (to be continued) | ||
