When two members of the same species differ from each other in their MHC-encoded antigens, mixing their lymphocytes leads to a vigorous T-cell response. This is the phenomenon of alloreactivity, exemplified here as a mixed lymphocyte response. In this article Michael Bevan presents a hypothesis to aecount for alloreaetivity, based on the notion that the alloreactive target determinant is a sequence or conforrnational determinant contributed entirely by the foreign MHC molecule in isolation, which is expressed at high density on the antigen-presenting cell.

MHC antigens have a unique ability to stimulate alloreactivity; it has been estimated that in the mixed lymphocyte response somewhere between 0.5 and 10% ofT cells can respond to stimulator cells expressing foreign MHC antigens, whereas the fraction of T cells that can respond to non-MHC antigens is probably at least 100-fold lower than this 1, 2. Cytotoxic T lymphocytes respond strongly to class-I MHC differences while helper T cells respond vigorously to class-II differences. The response to foreign MHC is specific: when T cells from strain A are stimulated with cells from strain B the responding cells are, by and large, a separate set of clones from those responding to the MHC antigens of strain C or strain D; there is, of course, some overlap or cross-reactivity. Alloreactivity has been known and investigated for decades but in the 1970s the discovery of MHC-restriction of T-cell recognition provided a more physiological role for MHC antigens. This important property of T lymphocytes, which distinguishes them from B cells, is that they do not recognize foreign antigens such as viruses or soluble protein antigens or any other non-MHC antigen in isolation, but recognize and respond to them only in association with MHC antigens on the antigenpresenting cells. Cytotoxic T cells recognize antigen plus class-I molecules while helper cells recognize antigen in