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Doherty and Zinkernagel inoculated mice with a virus causing meningitis. They isolated the immune T killer cells and found that these had to recognize two things on the surface of the infected cells in order to kill them: virus antigen, as expected, but also an MHC molecule of the infected mouse strain. MHC molecules are normal components of healthy cells. They were known to differ among individuals and to cause rejection of organ transplants and they are therefore sometimes called transplantation antigens. It came as a surprise that they were also involved in recognition of infected cells.

Doherty and Zinkernagel presented two main theoretical models to explain their observations. These models have inspired immunologists and set the stage for research on cell-mediated immunity for at least two decades.

Wrong combination: the right virus antigen (x) but the wrong MHC molecule (b).
Wrong combination again: the right MHC molecule (a) but the wrong virus antigen (y).
The correct combination or virus antigen (x) and MHC molecule (a) leads to killer cell attack.
 A T killer cell (upper right) attaching to and sensing the antigens on a target cell. If the target cell carries the correct antigens fitting the receptor of this particular T cell, the "kiss of death" will follow: the target cell will be destroyed.  

 

The "dual recognition" model assumed that two receptors on the T cell recognized virus antigen and the MHC molecule separately (best illustrated by the previous figure of the "correct combination").

The "altered self" model was based on one T-cell receptor recognizing an MHC molecule modified by virus antigen - or "a little bit of transplantation antigen, a little bit of virus," as Doherty and Zinkernagel have phrased it. (This is illustrated in the "zoom" above, like the previous model based on figures in the original reports.) Through important discoveries made later by other scientists, we are now getting a clearer picture of the scenario. The T-cell receptor, not yet identified at the time of the discovery, recognizes a small part of a virus protein, attached in a cleft formed by the transplantation antigen.





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