Helper CD4+ T cells (TH cells) acquire distinct phenotypes, depending on the prevailing cytokine environment, and two models exist to explain how this might occur. The first is an "instructive" model, which proposes that cytokines direct cell fate by launching a program of differentiation and gene transcription. The second is a "selective" model that suggests that T cells undergo an essentially stochastic fate determination that is then supported by the appropriate set of cytokines. Mullen et al. present evidence for a selective model of TH1 development. They demonstrate that expression of the hallmark TH1 cytokine interferon-γ (IFN-γ) and a recently identified master regulator gene, T-bet, are independent of interleukin-12 (IL-12) and the associated protein STAT-4 (signal transducer and activator of transcription 4). Retroviral expression of T-bet directly initiated IL-12-autonomous induction of IFN-γ expression, which could then be secured with the provision of an IL-12/Stat-4 signal. The stabilization of IFN-γ expression by IL-12/Stat-4 correlated with the activity of CBP (CREB-binding protein), a cofactor with intrinsic acetyltransferase and chromatin-remodeling activity. These findings suggest that cytokines may be critical in nurturing committed TH cells, rather than dictating to those that have not yet made a decision.
A. C. Mullen, F. A. High, A. S. Hutchins, H. W. Lee, A. V. Villarino, D. M. Livingston, A. L. Kung, N. Cereb, T.-P. Yao, S. Y. Yang, S. L. Reiner, Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907-1910 (2001). [Abstract] [Full Text]