Unraveling a Revealing Paradox: Why Major Histocompatibility Complex I–signaled Thymocytes “Paradoxically” Appear as CD4(+)8(lo) Transitional Cells During Positive Selection of CD8(+) T Cells

The mechanism by which T cell receptor specificity determines the outcome of the CD4/CD8 lineage decision in the thymus is not known. An important clue is the fact that major histocompatibility complex (MHC)-I–signaled thymocytes paradoxically appear as CD4(+)8(lo) transitional cells during their differentiation into CD8(+) T cells. Lineage commitment is generally thought to occur at the CD4(+)8(+) (double positive) stage of differentiation and to result in silencing of the opposite coreceptor gene. From this perspective, the appearance of MHC-I–signaled thymocytes as CD4(+)8(lo) cells would be due to effects on CD8 surface protein expression, not CD8 gene expression. But contrary to this perspective, this study demonstrates that MHC-I–signaled thymocytes appear as CD4(+)8(lo) cells because of transient down-regulation of CD8 gene expression, not because of changes in CD8 surface protein expression or distribution. This study also demonstrates that initial cessation of CD8 gene expression in MHC-I–signaled thymocytes is not necessarily indicative of commitment to the CD4(+) T cell lineage, as such thymocytes retain the potential to differentiate into CD8(+) T cells. These results challenge classical concepts of lineage commitment but fulfill predictions of the kinetic signaling model.