Making a commitment

T-bet, a member of the T-box family of transcription factors, has been implicated in the regulation of T-helper type 1 and 2 (T_H1 and T_H2) lineage commitment of CD4⁺ T cells. Two papers in Science by Laurie Glimcher and co-workers now show that mice lacking T-bet spontaneously develop an asthma-like phenotype and that T-bet is required for the control of interferon-γ (IFN-γ) production in CD4⁺ T cells and natural killer (NK) cells but, unexpectedly, not in CD8⁺ T cells.

Human asthma is characterized by airway inflammation, airway hyper-responsiveness (AHR) and airway remodelling, and is associated with infiltration by T_H2 cells. T-bet transactivates the gene that encodes IFN-γ in T_H1 cells and suppresses the development of T_H2 cells. In the first paper, the group looked at the role of T-bet in asthma and observed that patients with allergic asthma had lower expression of T-bet in their lungs than non-asthmatics. To investigate the role of T-bet in asthma, T-bet-deficient mice were generated and examined for signs of asthma. T-bet^−/− mice, in the absence of any immunogenic stimulation, spontaneously developed AHR and exhibited features of airway remodelling.

The second paper focused on the role of T-bet in the transcriptional control of IFN-γ production. Previous studies showed that T-bet production correlates with IFN-γ production in all cells examined but the mechanisms of control remain poorly understood. To investigate the role of endogenous T-bet in controlling IFN-γ production in CD4⁺ T cells, cells were isolated from T-bet^−/− mice and stimulated with anti-CD3 and anti-CD28 antibodies. IFN-γ production was decreased in cells lacking T-bet, even in the presence of interleukin-12 (IL-12), which is a potent stimulator of IFN-γ production. Next, they addressed the role of T-bet in T_H1–T_H2 polarization. CD4⁺ T cells were cultured under neutral or polarizing conditions and the phenotype of the effector T cells was examined by detecting cytokine production. When stimulated under T_H1-inducing conditions, T-bet^−/− cells produced less IFN-γ and more IL-4 and IL-5, indicating that they had instead developed a T_H2 phenotype.

Further evidence of defective T_H1 development in T-bet^−/− mice came from experiments in which they were infected with Leishmania major, a protozoan that requires a T_H1 response to resolve infection. C57BL/6 mice can control infection but BALB/c mice develop a T_H2 response and are susceptible to infection. When T-bet was knocked out in the resistant C57BL/6 background, the mice became infected and failed to control the infection.

Is T-bet essential for IFN-γ production in cells other than CD4⁺ T cells? NK cells produce IFN-γ in response to stimulation with IL-12 and IL-18, but T-bet^−/− NK cells produce less IFN-γ than wild-type cells and their effector function is also impaired. In contrast to CD4⁺ and NK cells, T-bet^−/− CD8⁺ T cells stimulated with cytokines produced similar amounts of IFN-γ to wild-type CD8⁺ T cells. This result was surprising, because a previous study had shown that retroviral transduction of T-bet into type-2 CD8⁺ T cells converted them into type-1 cells.

These results indicate that the T-bet^−/− mouse is a new model for asthma, and confirm the crucial role of T-bet in T_H1 lineage commitment. However, surprisingly, the transcriptional control of IFN-γ production seems to be different in CD4⁺ and CD8⁺ T cells.