Enhanced T Cell Maturation and Altered Lineage Commitment in T Cell Receptor/CD4-Transgenic Mice

The two mature subsets of T lymphocytes, CD4+ and CD8+ cells arise from a common progenitor during development in the thymus. The differentiation of this progenitor cell into one of the two mature T cell subsets is determined by the specificity of the αβ TCR for MHC class I or class II molecules. Using a line of TCR-transgenic mice expressing an MHC class II-specific TCR, 2B4, we have examined the thymocyte subsets present in a selecting versus a nonselecting MHC background. Our results are consistent with the model that CD4 versus CD8 downregulation occurs stochastically. In an effort to confirm these findings, we examined T cell development in double-transgenic mice expressing high levels of a CD4-transgene plus the 2B4 TCR transgenes. Unlike the findings with MHC class I-specific TCR-transgenic models, peripheral T cells in these mice include a substantial fraction of MHC class II-specific (2B4+) T cells expressing CD8 plus the transgene-encoded CD4. In addition, analysis of both thymocytes and peripheral T cells in these double-transgenic mice indicate that CD4 overexpression also leads to a striking enhancement of T cell maturation in 2B4 TCR-transgenic mice. Together with the studies of others, these data support a stochastic model for CD4 versus CD8 lineage commitment of an MHC class II-specific TCR during T cell development in the thymus.