Cytotoxic T cell responses in HLA-A2.1 transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a restriction element.
Previous studies have indicated that the frequency of murine CTL precursors (CTLp) for human class I molecules is one to two orders of magnitude lower than that for murine class I alloantigens, and that this is due to species-specific structural differences between these molecules. Transgenic mice expressing the human class I MHC Ag HLA-A2.1 were used to examine changes in the frequency of class I HLA-specific precursors after T cell differentiation in an HLA-A2.1 positive environment. The HLA-A2.1 gene product was expressed at levels comparable to those of the endogenous H-2Db molecule in thymus, bone marrow, and spleen. By limiting dilution analysis, it was observed that the frequencies of CTLp in transgenic mice responding to the human alloantigens HLA-B7 or HLA-A2.2 were comparable to or lower than those in normal C57BL/6 mice, regardless of whether the Ag was presented on human or murine cells. Thus, expression of a human class I molecule in these animals did not result in an expansion of the number of CTLp specific for other human class I Ag. In addition, the frequency of HLA-A2.1-restricted, influenza specific CTLp was substantially lower than the frequency of H-2b restricted CTLp, indicating a poor utilization of HLA-A2.1 as a restricting element. Finally, the frequencies of CTLp for HLA-A2.1 expressed on syngeneic murine tumor cells were decreased significantly. Thus, expression of HLA-A2.1 in these animals appeared to induced tolerance to this Ag. Interestingly, however, these mice were not tolerant to the HLA-A2.1 molecule expressed on human cells. This indicates that the HLA-A2.1 associated epitopes expressed on murine and human cells differ and suggests that, under these circumstances, HLA-A2.1 acts as a restricting element for human nominal Ag. These results are discussed in the context of current models of T cell repertoire development.
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Department of Surgery, University of Virginia Medical Center, Charlottesville 22908.
Bernhard
E J
EJ
Holterman
M J
MJ
Strub
S
S
Parham
P
P
Lacy
E
E
Engelhard
V H
VH
D000818:Animals; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000032:analysis; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000032:analysis; D015793:HLA-B7 Antigen; D006801:Humans; D007108:Immune Tolerance; D009980:Influenza A virus / Q000276:immunology; D007958:Leukocyte Count; D008221:Lymphoid Tissue / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology*; D013045:Species Specificity; D013234:Stem Cells / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000939:Epitopes; D006183:H-2 Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015793:HLA-B7 Antigen