Quantitative but Not Qualitative Variation in MHC Class II Alters CD4 Interaction and Influences T Cell Repertoire Formation

The influence of the interaction between CD4 and MHC class II molecules on selection of the T cell repertoire was studied in transgenic mice expressing human or human/mouse hybrid MHC class II β chains. Either wild-type DRβ chains (DR1β) or hybrid β chains comprising the β1 domain of DR and the β2, transmembrane, and intracytoplasmic domains of I-E (DRβ1Eβ2) were introduced into and expressed in transgenic mice as a heterodimer with endogenous I-Eα. Mice expressing low levels of DR1β:I-Eα or those expressing low or higher levels of the hybrid DRβ1Eβ2:I-Eα were studied. Immunization with a suboptimal dose of influenza nucleoprotein peptide exposed a fivefold lower frequency of DR-restricted, peptide-specific, IL-2-secreting T cells in the mice with low-level expression of DRβ1Eβ2:I-Eα when compared to mice expressing the same molecule at higher levels. The frequency in DRβ wild-type mice was only twofold lower than that measured in mice with comparable levels of expression of DRβ1Eβ2. These results suggest that positive selection is sensitive to quantitative variation in MHC class II density, unmasked when antigen is limiting, but is relatively insensitive to qualitative variation in the MHC class II: CD4 interaction.