Duration and Strength of Extracellular Signal-Regulated Kinase Signals Are Altered During Positive Versus Negative Thymocyte Selection

Abstract

During thymocyte development, high-affinity/avidity TCR engagement leads to the induction of negative selection and apoptosis, while lower TCR affinity-avidity interactions lead to positive selection and survival. To elucidate how these extracellular interactions are translated into intracellular signals that distinguish between positive and negative selection, we developed a culture system in which naive double-positive thymocytes were either induced to differentiate along the CD8+ lineage pathway or were triggered for clonal deletion. Using this system, we show that sustained low level activation of extracellular signal-regulated kinases (ERKs) promotes positive selection, whereas strong but transient ERK activation is coupled with negatively selecting stimuli. Importantly, similar ERK activation profiles were demonstrated during positive selection for strong agonist ligands presented at low concentrations or weak agonist ligands. This is consistent with the affinity/avidity model and a role for strong or weak agonists during positive selection. Surprisingly, the addition of a pharmacological inhibitor which blocks ERK activation prevented the induction of negative selection. These data suggest that the duration and strength of the TCR signal is involved in discriminating between positive and negative selection.

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ

“…Transient but robust Erk1/2 activation after strong engagement of TCR in DP thymocytes induces negative selection. By contrast, weaker but prolonged Erk1/2 activation after low-affinity engagement of TCR in DP thymocytes promotes positive selection (14,16,17). The Ras and Erk1/2 activation in DGK␣ Ϫ/Ϫ Ϫ/Ϫ DP thymocytes is enhanced which could convert positive selection into negative selection.…”

“…IP 3 and DAG induce activation of the Ca 2ϩ -calcineurin and RasGRP1-Ras-Erk1/2 cascades. Ras and Erk1/2 have been implicated in both positive selection and negative selection (12)(13)(14)(15)(16)(17). Recent evidence indicates that DGK␣ and , isoforms known to be expressed in T cells negatively control DAG and the Ras-Erk1/2 signaling pathway after TCR engagement (18)(19)(20)(21)(22).…”

B-Raf Contributes to Sustained Extracellular Signal-regulated Kinase Activation Associated with Interleukin-2 Production Stimulated through the T Cell Receptor

“…A similar phenomenon was found in T cells. Mariathasan et al (52) demonstrated that in thymocytes, negatively selecting stimuli by agonistic peptides through TCR induced transient and strong ERK activation, resulting in cell death, whereas positively selecting stimuli by the analogue peptides induced sustained and weak ERK activation, resulting in cell survival. In a very recent study, it has been reported that B-Raf but not Raf-1 was activated with TCR stimulation in CD4 ϩ CD8 ϩ double positive thymocytes (53).…”

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

“…As in other cell types, the duration of Erk signaling plays a decisive role in multiple T cell outcomes: positive versus negative selection of thymocytes (1,2), CD4 versus CD8 lineage commitment (3), response to low-affinity versus high-affinity Ags in mature T cells (4), or Th1 versus Th2 differentiation of effector T cells (5). These developmental or differentiation processes are initiated by signaling through the TCR (6,7).…”