Coreceptor reversal in the thymus: Signaled CD4(+)8(+) thymocytes initially terminate CD8 transcription even when differentiating into CD8(+) T cells

A central paradigm of T cell development is that CD4(+)8(+) (DP) thymocytes differentiate into CD4(+) or CD8(+) T cells in response to intrathymic sig nals that extinguish transcription of the inappropriate coreceptor molecule . Contrary to this prevailing paradigm, we now demonstrate that signaled DP thymocytes initially terminate CD8 transcription even when differentiating into CD8(+) T cells. Remarkably, thymocytes that have selectively terminat ed CD8 transcription can be signaled by IL-7 to differentiate into CD8(+) T cells by silencing CD4 transcription and reinitiating CD8 transcription, e vents we refer to as "coreceptor reversal." These observations significantl y alter our understanding of CD8(+) T cell differentiation and lead to a ne w perspective ("kinetic signaling") on CD4/CD8 lineage determination in the thymus. These observations also suggest a novel mechanism by which bipoten tial cells throughout development can determine their appropriate cell fate .