Some examples of these are, but are not limited to, T-bet, GATA-3, interferon regulatory factor family and Foxp3.90,91 These transcription factors play an important role in the differentiation of T cells, but

are beyond the scope of this review. So far, we have reviewed the transcription factors that are activated downstream find more of TCR signalling and how components of the immunological synapse activate them. T cells can differentiate to perform various effector functions, be tolerized or be deleted. All these processes require engagement of TCRs by peptide–MHC complexes and happen over days. Tolerance induction can occur when TCR signals are delivered in the absence of co-stimulatory signals, whereas deletion can occur when high-affinity self-peptide KU-60019 molecular weight interactions occur in the periphery.21 Effector T-cell differentiation occurs as a result of co-operation between TCR, co-stimulatory and cytokine signals.92,93 Differentiation is also accompanied by epigenetic changes occurring at specific promoters, particularly

in the promoters of cytokine genes.9,94 Antigen dose and affinity, however, also play an important role in determining the differentiation state of effector T cells in the absence of polarizing cytokines. O’Garra and colleagues demonstrated that increasing antigen dose led to more IFN-γ production by T cells whereas very low or very high antigen doses caused cells to produce

IL-4.95 Another study, from Bottomly and colleagues, showed that a high dose led to IFN-γ-producing cells whereas stimulation with a lower antigen Oxymatrine dose caused cells to produce IL-4.96 A requirement for co-stimulation through CD28 was demonstrated in this system for Th2 responses by way of weak TCR signals.97 Although peptide dose and affinity do show an impact on Th1 versus Th2 choices, Croft and colleagues demonstrated that the time of differentiation also played an important role in determining whether cells produced IL-4 or IFN-γ.98 Bottomly and colleagues also demonstrated that antigen dose affected the balance of NFATp versus NFATc DNA-binding activity, with lower potency ligands favouring higher levels of nuclear NFATc and lower levels of NFATp conducive for IL-4 transcription.99 More recently, Paul and colleagues have explored the mechanism by which high and low doses of peptide induce Th1 versus Th2 responses. They report that T cells stimulated by low peptide concentrations result in IL-2-dependent signal transducer and activator or transcription 5 (STAT5) phosphorylation, TCR-induced IL-4-independent early GATA-3 expression and IL-4 production. Stimulation with a higher concentration of peptide caused, by way of the ERK pathway, abrogation of GATA-3 expression and IL-2-dependent STAT5 phosphorylation and IL-4 production.