MHCrestricted responses to minor H antigens in vivo and in vitro

In the mid-1970s, several months after MHC-restricted responses to viruses by cytotoxic T cells were first reported by Zinkernagel and Doherty, two laboratories reported similar MHC-restricted cytotoxic T cell responses specific for minor H antigens. One was that of Bevan, who in secondary mixed lymphocyte culture (MLC), raised MHC-restricted responses to the multiple H antigens by which two MHC-matched inbred strains differed. The other was that of Simpson, who likewise found cytotoxic T cell responses in secondary MLC to the male-specific transplantation antigen, H-Y, to be MHC-restricted.

Subsequently, MHC-restricted minor H-specific cytotoxic T cell responses have been obtained by immunizations between minor H congenic and their recipient parental strains. Alleles of loci stimulating rapid in vivo responses generally give good cytotoxic T cell responses following secondary MLC in vitro but the strongest in vitro responses are obtained from MHC-matched strains differing at multiple minor H loci, presumably due to the activation of a large number of different clones of different specificities. Both Tomonari and Roopenian have isolated T cell clones specific for various minor H antigens present on the immunizing cell from murine secondary MLC and these include not only class I-restricted CD8 but also class Il-restricted CD4 clones.

The work of Matzinger has shown that in vivo responses to minor H antigens are also MHC-restricted. There is good evidence that both in vivo and in vitro it is necessary to have concomitant activation of both CD8+ and CD4+ T cell subpopulations in order to generate either a graft rejection or a cytotoxic T cell response against minor H antigens.

As a corollary, at least two epitopes, restricted respectively by MHC class I and II molecules, and probably encoded by different genes, are necessary to stimulate in vivo graft rejection. This has been demonstrated in mice by genetic and molecular genetic approaches.

In humans, the genetic analysis of T cell responses to minor H antigens is much more difficult, because here we are dealing with an outbred population in which the MHC restriction elements (HLA encoded) necessary for the recognition of the minor H antigen are independently segregating, and it is likely that individuals will be heterozygous for alleles of transplantation antigens. Human families are also small and one cannot do the genetic experiments possible in mice. However, it is quite clear from clinical interventions involving exchange of organs or tissues between MHC-matched but genetically non-identical humans that graft rejection responses include components directed against transplantation antigens encoded outside the MHC. Thus, it is still necessary to use immunosuppression for kidney grafts from HLA-matched donors and for bone marrow transplants from HLA-matched siblings which can give rise to intractable graft-versus-host disease directed against non-MHC transplantation antigens. It is from such patients that Goulmy has isolated in vitro HLA-restricted T cell clones with specificities that look remarkably similar to those of the minor H antigens in mouse. One such specificity is the male-specific minor H antigen, H-Y, others are five specificities named HA-1 to HA-5 whose segregation in families and in unrelated individuals expressing the appropriate HLA restriction molecules has been studied.

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