Tenuous paths in unexplored territory: From T cell receptor signaling to effector gene expression during thymocyte selection

Abstract

During the last step of alphabeta T cell development, thymocytes that have rearranged genes encoding TCR chains and express CD4 and CD8 coreceptors are selected on the basis of their TCR reactivity to escape programmed cell death and become mature CD4 or CD8 T cells. This process is triggered by intrathymic TCR signaling, that activates 'sensor' transcription factors 'constitutively' expressed in DP thymocytes. Eventually, TCR-signaled thymocytes evolve effector transcriptional circuits that control basal metabolism, migration, survival and initiation of lineage-specific gene expression. This review examines how components of the 'sensing' transcription apparatus responds to positive selection signals, and highlights important differences with mature T cell responses. In a second part, we evaluate current observations and hypotheses on the connections between sensing transcription factors and effector circuitries.

Figure 1

Schematic representation of the Erk-Elk (green) and calcineurin-NFAT (blue) sensor modules in thymocytes. Plain arrows indicate activation, dashed arrows nuclear import. The membrane-proximal signaling event that lead to PLCγ 1 activation are not depicted. Active PLCγ 1 releases inositol triphosphate and diacyl glycerol, which cause calcium release from intra-cellular stores (and the ensuing opening of plasma membrane CRAC channels) and activation of Ras via the exchange factor RasGRP1 [157,158], respectively.

Figure 2

Foxo1 as a sensor for TCR and IL-7 signals in thymocytes. In mature T cells, IL-7 activates PI-3 kinase and Akt, thereby causing Foxo1 phosphorylation. As Foxo1 promotes IL-7Rα expression, IL-7-mediated Foxo1 phosphorylation contributes to repress IL-7Rα expression and thereby IL-7 signaling. In SP thymocytes, where Foxo1 also promotes IL-7Rα expression, both TCR signaling and IL-7 signaling potentially contribute to PI-3 kinase activation. This mechanism could have a ‘licensing’ function by preventing the terminal maturation of SP thymocytes unable to cease TCR signaling. In tumor cells, IKKβ has been shown to phosphorylate Foxo3 and prevent its nuclear translocation [145]; it is not yet known which stimulus activates IKKβ, and whether it also acts on Foxo1 in thymocytes or T cells.