14: Role of MHC Molecules in Defense Against Virus
A number of years ago Zinkernagel and Doherty[33] made a major discovery concerning the way animals defend themselves against viruses. Consider two animals, A and B. They are bred so they differ in their histocompatibility genes. ZD discovered that when A animals were infected with virus a, they produced T cells that could kill a-infected cells from an animal with the same MHC genes as A, but not cells from a B animal when infected with virus a. That is, when cells from B were infected with a the T cells from infected A had no effect, an all or none difference.
If A and B were identical twins T cells from A infected with a would kill cells from B infected with a. The effect was also virus specific. Clearly the target for defense (killing infected cells) required a joint target, something from the cell being attacked (MHC molecules) and something from the virus. When my lab got interested in this subject, the molecular mechanism for this specificity was in a great state of confusion. My own level of confusion is illustrated by (264), in which we looked for specific interactions between viral proteins and MHC molecules on a liposome surface, and found none. At some point evidence was obtained elsewhere that the viral target was a complex between a viral peptide antigen and an MHC molecule. No one was convinced of this at the time (Don Wiley, private communication, and a host of others.) My lab tried very hard to prove this, first with laser energy transfer methods – see (311).
Some background: At this point, I knew very little practical immunology, and everyone in the lab knew that. It was distressing to me that one graduate student, who had experience in immunology, thought this was all a dumb idea, and he went around the lab discouraging other students. At this stage, many labs tried unsuccessfully to show that MHC peptide complexes could stimulate specific T cells. Tania Watts in my lab did succeed, and gave the results at a Gordon Conference. See (297). Moreover, she demonstrated binding of specific antigenic particles to the appropriate MHC in liposomes and supported bilayers. See (323). This demonstrated for the first time that specific peptide and specific MHC in lipid membranes were sufficient to trigger a biological response from a specific T-cell!! This was a great day for a “physical chemistry” lab. See also Chapter 15, 16 and 18 for studies related to antigen presentation.
In my first application to the NIH for immunology research support, a reviewer commented “McConnell may be a great physical chemist, but he surely does not know much about immunology”. That was certainly true at the time, but with the help of my students and the NIH I did quickly become more knowledgeable about the field. I consequently trained a number of chemists who now have solid foundations in physical chemistry as well as immunology.
Chapter 15: Most Unusual Chemical Reactions
