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Alterations in CD4-Binding Regions of the MHC Class II Molecule I-E^k Do Not Impede CD4⁺ T Cell Development¹

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

The T cell coreceptors CD4 and CD8 enhance T cell responses to TCR signals by participating in complexes containing TCR, coreceptor, and MHC molecules. These ternary complexes are also hypothesized to play a seminal role during T cell development, although the precise timing, frequency, and consequences of TCR-coreceptor-MHC interactions during positive selection and lineage commitment remain unclear. To address these issues, we designed transgenic mice expressing mutant I-E^k molecules with reduced CD4-binding capability. These transgenic lines were crossed to three different lines of I-E^k-specific TCR transgenic mice, and the efficiency of production of CD4⁺ lineage cells in the doubly transgenic progeny was assessed. Surprisingly, replacing wild-type I-E^k molecules with these mutant molecules did not affect the production of CD4⁺CD8^- thymocytes or CD4⁺ peripheral T cells expressing any of the three TCRs examined. These data, when considered together with other experiments addressing the role of coreceptor during development, suggest that not all MHC class II-specific thymocytes require optimal and simultaneous TCR-CD4-MHC interactions to mature. Alternatively, it is possible that these particular alterations of I-E^k do not disrupt the CD4-MHC interaction adequately, potentially indicating functional differences between I-A and I-E MHC class II molecules.

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