T-bet: a bridge between innate and adaptive immunity

Key Points T-bet is expressed in many different cell types of the innate and adaptive immune system in both myeloid and lymphoid lineages. T-bet expression arose early in evolution, before the appearance of the adaptive immune system, which suggests that its function in B cells and T cells may partly reflect coopted transcriptional pathways. T-bet has a crucial role in regulating mucosal homeostasis, mainly via its function in dendritic cells and innate lymphoid cells. T-bet regulates the T helper 1 (T H 1) cell differentiation programme by recruiting chromatin-modifying enzymes, which promote permissive chromatin marks at T H 1 cell-specific loci by directly regulating the expression of interferon-γ ( Ifng ) and approximately 27 T H 1 cell-specific genes, and by organizing the three-dimensional architecture of the Ifng locus. T-bet blocks the differentiation of other CD4 + T H cell subsets either by inhibiting the expression of T H cell lineage-specifying transcription factors in T H precursor cells or by interfering with their transcriptional activity. T-bet expression in other fully differentiated T H cell subsets results in the acquisition of the T H 1 cell phenotype, which may or may not be accompanied by the repression of the existing gene expression profile. During acute infections, T-bet balances terminal differentiation and memory cell potential in both CD4 + and CD8 + T cells. Its expression correlates with the terminal differentiation of CD4 + and CD8 + T effector cells, and its absence correlates with higher memory cell potential. During chronic infections,T-bet expression in CD8 + T cells prevents cell exhaustion. The transcription factor T-bet is best known to immunologists as a master regulator of T helper 1 cell differentiation. However, it is becoming apparent that T-bet has important functions in other leukocyte populations, including memory CD8 + T cells, B cells, innate lymphoid cells, dendritic cells and natural killer cells. This Review discusses these emerging immunological roles for T-bet. Originally described over a decade ago as a T cell transcription factor regulating T helper 1 cell lineage commitment, T-bet is now recognized as having an important role in many cells of the adaptive and innate immune system. T-bet has a fundamental role in coordinating type 1 immune responses by controlling a network of genetic programmes that regulate the development of certain immune cells and the effector functions of others. Many of these tr