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Timing Is Everything
As they develop into mature CD4+ or CD8+ single-positive (SP) T cells in the thymus, immature thymocytes undergo positive selection, during which they have both CD4 and CD8 [double-positive (DP) cells] and their T cell antigen receptor (TCR) is stimulated by self-peptide–major histocompatibility complexes. It remains unclear whether it is the strength or the duration of TCR signaling that determines how a cell “chooses” to become a CD4+ or CD8+ SP cell (see the Perspective by Alarcón and van Santen). Saini et al. generated transgenic mice that expressed an inducible gene encoding the tyrosine kinase Zap70, a critical mediator of TCR signaling, in a Zap70-deficient background (TetZap70 mice). Thymocytes in Zap70-deficient mice are arrested at the DP stage because of defective TCR signaling, but this block was removed by induction of Zap70 expression in the TetZap70 mice, after which CD4+ SP cells developed more quickly than did CD8+ SP cells. The temporal difference in SP cell development, also seen in wild-type mice, occurred because CD4+ SP cells required less Zap70 protein to develop than did CD8+ SP cells. In addition, this study showed that DP thymocytes were heterogeneous, with CD4+ and CD8+ SP cells arising from different DP subpopulations. Together, these data suggest that regulation of the abundance of Zap70 enables the temporal differential development of CD4+ and CD8+ cells, which is based on signal strength through the TCR, thus incorporating both the “strength” and the “duration” models of positive selection.
