More than just a T-box: the role of T-bet as a possible biomarker and therapeutic target in autoimmune diseases

Abstract

T-bet was initially described as a T-box transcription factor with an essential role in orchestrating Th1 cell differentiation. Subsequently, it was determined that T-bet controls the expression of numerous cytokines and their receptors, adhesion molecules and chemokine receptors, and therefore determines the differentiation and development status of many types of immune cells. The critical role of T-bet in autoimmune diseases, particularly multiple sclerosis and its animal model experimental autoimmune encephalomyelitis, implicates it as a potential biomarker for pathogenic T cells as well as a therapeutic drug target.

Figure 1. Role of T-bet as a transcription factor in the differentiation of T cells

(A) T-bet is a key regulator of the Th1 differentiation of CD4⁺ T cells. Once induced by the IFN-γ–STAT1 signaling pathway, T-bet promotes the transcription of IFN-γ and induces Runx3 and IL-12Rβ2 expression. IFN-γ can also enhance T-bet expression in a positive-feedback loop. Runx3 maintains the maximal production of IFN-γ and silences the IL-4-encoding gene. The completion of Th1 development requires IL-12–STAT4 signaling as well as the suppression of the Th2 differentiation-related transcription factor GATA-3 by T-bet. (B) T-bet is involved in the early induction of IFN-γ in the development of cytotoxic CD8⁺ effector T cells. Upon stimulation via the TCR, T-bet is induced and subsequently induces the transcription of IFN-γ. The transcription factor, Runx3, induces Eomes and then synergistically induces and maintains the production of IFN-γ, as well as the expression of granzyme B and perforin. Eomes: Eomesodermin; IFN-γR: IFN-γ receptor; IL-12Rβ2: IL-12 receptor β2; TCR: T-cell receptor.