In Vitro and in Vivo Evidence for High Frequency of I-A^b-Reactive CD4⁺ T Cells in HLA-DQ or HLA-DRA Transgenic Mice Lacking Endogenous MHC Class I and/or Class II Expression

Although T cells are educated to recognize foreign antigenic peptides in the context of self MHC molecules during their development in the thymus, peripheral T cells also recognize allo- and xeno-MHC molecules. The lower frequency of xeno-MHC-reactive T cells than that of allo-MHC-reactive T cells is often explained by the difference in the degree of homology between xeno- or allo-MHC and self MHC molecules, as well as by the species barrier of the molecules involved in immune recognition. To distinguish these two possibilities, we estimated the frequency of I-A^b-reactive CD4⁺ T cells selected by HLA-DQ or DRαEβ^b molecules, using HLA-DQ6 and HLA-DRA transgenic C57BL/6 (B6) mice lacking endogenous MHC class I and/or class II molecules (DQ6A^% and DRα30A^%β₂^%). CD4⁺ lymph node T cells from DQ6A^% and DRα30A^%β₂^% showed the strong proliferative response to I-A^b molecules. In addition, DQ6A^% and DRα30A^%β₂^% rejected the skin graft from mice expressing I-A^b molecules irrespective of MHC class I expression, indicating that the CD4⁺ T cells recognizing I-A^b molecules are directly involved in this rejection. The estimated frequency of I-A^b-reactive CD4⁺CD8^- thymocytes in DRα30A^%β₂^% and DQ6A^% was comparable with that observed in the MHC class II-disparate strains. Our findings thus indicate that CD4⁺ T cells selected to mature on xeno-MHC class II molecules such as HLA-DQ6 or DRαEβ^b, when these molecules are expressed in mice, recognize I-A^b molecules as allo-MHC class II, despite the less structural homology.