Fine-tuning T cell receptor signaling to control T cell development

Abstract

T cell development from immature CD4(+)CD8(+) double-positive (DP) thymocytes to the mature CD4 or CD8 single-positive (SP) stage requires proper T cell receptor (TCR) signaling. The current working model of thymocyte development is that the strength of the TCR-mediated signal - from little-or-none, through intermediate, to strong - received by the immature cells determines whether they will undergo death by neglect, positive selection, or negative selection, respectively. In recent years, several developmentally regulated, stage-specifically expressed proteins and miRNAs have been found that act like fine-tuners for signal transduction and propagation downstream of the TCR. This allows them to govern thymocyte positive selection. Here, we summarize recent findings on these molecules and suggest new concepts of TCR positive-selection signaling.

Keywords: T cell development; Tespa1; Themis; miR-181; signaling; thymocyte; voltage-gated sodium channel.

Figure 1

Proteins affecting signaling during thymocyte positive selection. During thymocyte development, upon TCR interaction with self-MHCp complex, a cascade of signaling events is triggered. This process includes a series of tyrosine phosphorylations mediated by protein tyrosine kinases (e.g. Lck and ZAP-70), sequential signaling complex formation mediated by scaffold proteins (e.g., LAT and SLP-76), and more downstream diversified signaling pathways (e.g., ERK and NFAT). Over the past 30 years, many molecules important for thymocyte positive selection were discovered, characterized, and put in the context of the signaling network shown here. Recently, some newly identified molecules were found to be specifically involved in thymocyte positive selection (i.e., Themis, Tespa1, and VGSC). These each serve different functions in signaling in positive selection, acting with other molecules that may have a more general role in T cell signal transduction and negative selection. Insert. Model for GRB2-Themis-SHP1 complex association with LAT. Upon TCR stimulation during thymocyte positive selection, the scaffold protein LAT is tyrosine phosphorylated at multiple sites, which serve as the docking sites for many SH2-domain-containing molecules. Among these LAT-binding molecules, the adaptor protein GRB2 has a central SH2 domain flanked by two SH3 domains. Recent studies showed that Themis binds the C-terminal SH3 domain of GRB2 via its proline-rich region, whereas SHP1 binds the SH2 domain of GRB2 via its C-terminal phosphotyrosines. Thus GRB2 brings Themis and SHP1 together, and Themis is required for activity of SHP1. Abbreviations: DAG, diacylglycerol; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; Gads, GRB2-related adapter protein 2; GRB2, Growth factor receptor-bound protein 2; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; Itk, interleukin-2-inducible T cell kinase; LAT, linker of activated T cells; Lck, lymphocyte-specific protein tyrosine kinase; MHCp, MHC peptide; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; PIP2, Phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PTP, protein tyrosine phosphatase; SH2, Src homology region 2 domain; SH3, Src homology region 3 domain; SHP1, Src homology region 2 domain-containing phosphatase-1; SLP-76, SH2 domain containing leukocyte protein of 76kDa; TCR, T cell receptor; Tespa1, thymocyte-expressed, positive selection–associated-1; Themis, thymocyte-expressed molecule involved in selection; VGSC, voltage-gated sodium channel; ZAP-70, zeta-chain-associated protein kinase of 70 kDa.