When Mosmann et al. first classified mouse CD4 T-cell clones according to the cytokines that they produced1 and showed that these subsets possessed different effector functions2 a new era in our understanding of immunology had begun. Since then, substantial effort has gone into understanding how T-cell subsets function in health and disease, the factors that govern their differentiation and more recently the characterization and function of regulatory T cells that control immune responses. Transforming growth factor-beta (TGF-b) is a pleiotropic cytokine that regulates diverse biological processes during development and homeostasis. In this issue of Immunology Smeltz et al. describe an unexpected effect of this cytokine on CD4 T-cell differentiation and IFN-c synthesis. 3 Extensive studies on T-cell subsets revealed that T helper 1 (Th1) and T helper 2 (Th2) cells were mutually exclusive and that IFN-c, the signature cytokine of Th1 cells, inhibited the growth of Th2 cells4 while IL-4, the cytokine that defines Th2 cells, was inhibitory for Th1 cells5. Furthermore, both of these subsets produced cytokines that served as autocrine growth factors—IL-2 for Th1 and IL-4 for Th2 cells6, 7. Historically IFN-c was the first cytokine to be identified that promoted Th1 responses4. IFN-c selectively induced naıve CD45RA, but not memory CD45RO, T cells to secrete IFN-c8 and express the Th1-specific transcription factor T-bet9. IL-4 appeared to be essential for Th2 development7. A further level of control was introduced by cytokines produced by antigen presenting cells (APC). APC derived IL-1210, 11 and IL-1812 work in synergy to promote Th1 cell differentiation. Interestingly, comparable Th2 promoting cytokines from APC have not been described but APC that are low IL-12 producers, as in the lung, appear to preferentially induce Th2 cells13. The IL-4 that is necessary for Th2 development may be derived from a subset of natural killer (NK) cells14 or from the CD4 T cells themselves15. In addition to extracellular cytokines, the nature of the T-cell receptor stimulus and the presence, or absence, of a costimulus also regulate T-cell differentiation: high affinity T-cell receptor–MHC peptide interactions leading to a Th1 response while low affinity lead to a Th2 cytokine profile16–19. To control aberrant immune responses there are, in addition, regulatory T cells. These include T regulatory 1 (Tr1) cells that make IL-10 which inhibits both Th120 and Th221 responses and T helper 3 cells (Th3) that promote IgA responses in the gastrointestinal tract via TGF-b22 and also inhibit Th1 and Th2 responses23, 24. TGF-b has also been shown to inhibit GATA-3 expression and Th2 development9 as well as airway Th2 cell induced inflammation21. It has also been shown that CD4-dominant negative TGF-bRII mice are unable to mount effective Th1 responses to pathogens such as Leishmania25 and suffer impaired immunity to tumors26. In this issue of the journal, Smeltz et al. demonstrate that, under certain circumstances, TGF-b can actually promote Th1 cell differentiation. 3 This runs counter to the prevailing vision of TGF-b as a Th1 as well as a Th2 inhibitory cytokine25. Smeltz et al. suggest that TGF-b mediates this effect by inhibiting IL-4, which is inhibitory for Th1 responses. Indeed, Lingnau et al. have shown that a combination of TGF-b and IL-4 induced IFN-c production in human CD4 T cells stimulated with antiab T-cell receptor (TcR) specific antibody27. Consistent with other reports9, Smeltz et al. also report that TGF-b inhibited GATA-3 gene expression and IL-4 synthesis, but also found that TGF-b augmented the generation of IFN-c producing cells. 3 They showed and that this …