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Michael Bevan
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Every mature T cell specifically recognizes a particular combination of self-MHC molecule bound to a foreign peptide antigen. However, newborn T cells do not start out with the ability to recognize these complexes. During development, T cells rearrange their T cell receptor (TCR) genes, thus generating a diverse repertoire that includes those that do not recognize self-MHC. Only those that bind to self-MHC survive in the thymus.
Groping in the dark
In the early 1970s, this picture of thymic selection was still being colored in. Immunologists were unaware that the antigens recognized by T cells were peptides bound to MHC molecules. And TCRs themselves would not be defined for another decade.
Despite these handicaps, Rolf Zinkernagel and Peter Doherty laid out the Nobel Prize–winning rules of what is now known as self-MHC restriction in 1973. They showed that antiviral T cells from an immunized mouse only recognized infected cells from other mice that shared the same type of MHC genes (1). Two theories were proposed to account for these data. The dual recognition hypothesis predicted that the antiviral T cells bore two receptors—one for a self-MHC molecule, and the other for the viral antigen (2). But Zinkernagel and Doherty preferred their own altered-self hypothesis, which proposed that the T cells bore a single receptor that recognized an MHC molecule that had been somehow altered by the viral infection.
Altering a theory
Michael Bevan, then a postdoctoral fellow at the Salk Institute (San Diego, CA), was intrigued by the altered-self theory. He had been studying differences in the genes encoding minor histocompatibility antigens (mHAs) that cause graft rejection even when donors and recipients are MHC matched. He found that recognition of target cells by T cells specific for mHA also followed the rules of MHC restriction.
"There were about 50 minor antigen-encoding genes known at the time. The idea that any or all of them were ‘altering’ the structure of MHC molecules seemed crazy," recalls Bevan. Nevertheless, he says, "The single receptor hypothesis was solid. I stayed loyal to it." He proposed that the T cells recognized self-MHC molecules that were associated with these mHAs and called it the antigen interaction hypothesis. The nature of this altering—the binding of peptides to self-MHC—would not be known for a few more years.
Minor changes to major complexes
Bevan was able to boost confidence in the altered-self theory by disproving the two-receptor hypothesis. He found that in the progeny of MHC-A and MHC-B mice, individual T cells recognized antigen on either MHC-A or MHC-B cells but not both. In the dual recognition theory, each T cell would have had receptors for both MHC molecules and thus would have recognized both targets.
As a further test of his theory, Bevan designed an assay in which cells that had either the correct MHC but the wrong mHA or vice versa competed with cells that had both the correct MHC and mHA as targets for killing by mHA-specific T cells. He found that both the correct MHC and mHA had to be on the same target cells to be recognized by the T cells. An enticing explanation for these data was that the self-MHC and the antigen were somehow interacting. Bevan published these results in the Journal of Experimental Medicine in 1975 (3).
Self-based selection
Bevan next explored how self-MHC molecules helped shape the T cell repertoire. A previous hypothesis suggested that T cells were selected in the thymus (4). Bevan tested this theory by injecting T cell precursors from the progeny of MHC-A and MHC-B parents into lymphocyte-deficient MHC-A recipients. Newly generated T cells from these mice recognized antigen-presenting target cells from MHC-A but not MHC-B mice. Furthermore, when the thymus of the progeny mouse was replaced with an MHC-A–only thymus, most of its T cells only recognized antigen bound to MHC-A cells (5). Bevan concluded that the MHC molecules in the thymus determine what MHC molecules will be recognized by the T cells.
The definition of the TCR structure finally vindicated the single receptor hypothesis (6). TCRs were later shown to recognize peptide fragments bound to MHC molecules on antigen-presenting cells (7).
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