Strong xenogeneic HLA response in transgenic mice after introducing an α3 domain into HLA B27

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Abstract
THE pronounced response by mouse T cells to the major histocom-patibility complex (MHC) class I antigens of the same species is characterized by a relatively large fraction of responding cells (reviewed in ref. 1). Responses to MHC class I allelles of other species are, however, generally much weaker2–5. T lymphocytes are positively selected on thymic MHC antigens, resulting in a T-cell repertoire with strong alloreactivity6. This has been explained in terms of a mouse T-cell repertoire that is not efficiently selected for recognition of HLA molecules owing to the absence of HLA in mice. Here we show that mice transgenic for HLA mount a T-cell response against allogeneic HLA that is no better than in normal mice. We decided instead to test whether the mouse accessory molecule Lyt-2 on cytotoxic T lymphocytes could interact efficiently with the α3 domain of HLA. To do this, we replaced the α3 domain of HLA-B27 by a murine α3 domain in a gene construct used to produce transgenic mice, and then used the spleen cells from these mice to stimulate normal mouse T cells. Under these conditions cytotoxic T lymphocytes were generated with the same frequency against xenogeneic HLA-B27 determinants as against allogeneic mouse class I antigens. These findings indicate that the normally weak xeno-MHC response is due to the inefficient interaction of the murine Lyt-2 accessory molecule with HLA class I, and not to limitations of the mouse T-cell repertoire.