Differential T-cell receptor signals for T helper cell programming

Abstract

Upon encounter with their cognate antigen, naive CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen-presenting cells, cytokines and co-stimulatory molecules. The strength of the T-cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength. This review examines the recent literature in this area and highlights important new developments in our understanding of Th cell differentiation and TCR signal strength.

Keywords: CD4 cell; T-cell receptors; regulatory T cells; signal transduction.

Figure 1

The activity of phosphatase and tensin homologue (PTEN) and Akt and Akt substrate specificity are modulated by T‐cell receptor (TCR) signal strength. High TCR signalling results in activation of CK2 kinase, which phosphorylates and inactivates PTEN. The degradation of PTEN protein via ubiquitination occurs through Nedd4. When PTEN is inactive, phosphorylation of Akt at both S473 and T308 sites occurs. T cells exposed to low TCR strength activate caspases that cleave PTEN to cause transient down‐regulation of PTEN but PTEN activity is maintained and Akt is only phosphorylated at the T308 site. The differential phosphorylation patterns result in different Akt substrates being targeted. For example, Foxo1 is only phosphorylated at T24 following high‐dose stimulation resulting in exclusion from the nucleus, which prevents Foxo1 from inducing expression of Foxp3 and PTEN. Different RNA processing factors are phosphorylated depending on dose and this results in different splicing patterns.