In vitro responses to HY

The skin graft rejection responses to H-Y implied cell-mediated immunity, as defined by Medawar for graft rejection responses by recipients of grafts from donors with much broader genetic disparities. However, the concomitant humoral immune responses, with the production of antibodies at least to MHC antigens, made the search for antibodies to H-Y a sensible one; had they been successful, the molecular characterization of the H-Y antigen would have been straightforward. However, despite a promising start by Goldberg and her colleagues, who in 1971 found in the serum of female mice immunized with male tissues factors which preferentially bound to sperm cells and epidermal cells from male mice, these proved to be of very low titer and difficult to work with. No satisfactory monoclonal antibodies ImAbs) specific for H-Y were produced from the time when mAbs were shown to be so useful for molecules which would otherwise never have been characterized. In retrospect, the logic which equated the specificity of the low titer, sperm-binding antibodies with the previously described male-specific minor transplantation antigen, H-Y, could be faulted but, at that time, with no other characteristics attributed to the H-Y chromosome (but see below) it was understandable.

Shortly after her work with putatively H-Y specific antibodies, Goldberg published the first paper showing that H-Y-specific cytotoxic T cells could be detected in vitro in the draining lymph nodes of female H-2b mice that had recently rejected a syngeneic male graft. Subsequently, the level of cytotoxicity found in such populations was shown by Simpson and colleagues to be raised following a secondary-mixed lymphocyte culture (MLC) step after the in vivo immunization, and they were the first to demonstrate that such H-Y-specific T cells were MHC restricted, in the same way that Bevan showed for cytotoxic T cells specific for other minor transplantation antigens. The ability to generate H-Y-specific T cells restricted by some but not all MHC molecules proved to be a very powerful way of analyzing the manner in which MHC genes acted as Ir genes and establishing that the Ir gene products were in fact the MHC molecules. The work with H-Y established that not only were MHC class II molecules the Ir gene products, as was clear from the pioneering Ir gene work of McDevitt and Benaceraff with T helper cell and antibody responses to synthetic polymers, but the MHC class I molecules were the products of Ir genes controlling cytotoxic class I-restricted (CDS) T cells. In humans, CD8+ cytotoxic T cell clones specific for H-Y and restricted by HLA class I molecules have been isolated by Goulmy from female patients rejecting tissues and organs from HLA-matched males.

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