Signals transduced by T cell antigen receptors (TCRs) have been shown to be critical for alphabeta and gammadelta T cell development, but their role in lineage determination remains poorly defined. Two models have been forwarded for alphabeta/gammadelta lineage choice: the instructive model and the stochastic model. Recent data, however, are inconsistent with either model. In this study, we devised an experimental system in which lineage fate was controlled exclusively by the gammadeltaTCR. We then analyzed the impact of TCR signal strength on alphabeta/gammadelta lineage development by altering the surface expression or signaling potential of the gammadeltaTCR complex. We found that increasing the gammadeltaTCR signal strength favored gammadelta lineage development, whereas weakening the gammadeltaTCR signal favored alphabeta lineage development. These results support a model in which the strength of the TCR signal is a critical determinant in the lineage fate decision.
During positive selection, thymocytes transition through a stage during which T cell receptor (TCR) signaling controls CD4 versus CD8 lineage choice and subsequent maturation. Here, we describe a new T cell specific protein, THEMIS, that performs a distinct function during this stage. In Themis -/-mice, thymocyte selection was impaired and the number of transitional CD4 + CD8 int thymocytes as well as CD4 and CD8 single positive thymocytes was decreased. Remarkably, although no overt TCR-proximal signaling deficiencies were detected, Themis -/-CD4 + CD8 int thymocytes exhibited developmental defects consistent with attenuated signaling that were reversible by increased TCR stimulation. These results identify THEMIS as a critical component of the T cell developmental program and suggest that THEMIS functions to sustain and/or integrate signals required for proper lineage commitment and maturation.
Key Points
Ldb1 complexes bind to and positively regulate the expression of a large number of erythroid genes including most known Gata1-regulated genes. Ldb1 complexes and Klf1 frequently bind together and coregulate erythroid gene expression.
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