Adaptive immune responses are directed by at least three different types of effector CD4 + T helper (T H ) cell, known as the T H 1-, T H 2- and T H 17-cell lineages 1 , each of which orchestrates the immune response to particu- lar classes of microorganisms through the production of distinct cytokines. For example, T H 1 cells produce interferon-γ (IFNγ) to stimulate the clearance of intra- cellular infections 2 , T H 2 cells produce interleukin-4 (IL-4), IL-5 and IL-13 to promote the elimination of helminth infections 2 and T H 17 cells produce IL-17, which leads to the recruitment of neutrophilic granulo- cytes and may promote the elimination of extracellular bacteria 1 . In addition to promoting immunity, T H -cell subsets can also mediate pathological responses: T H 1- and T H 17-cell responses can cause autoimmunity 3 , and excessive T H 2-cell responses are involved in allergic reactions 2 . The differentiation of the T H -cell subsets that are required to protect the host from an infectious agent is directed by antigen-presenting cells (APCs), which translate their recognition of specific microbial features into signals that instruct the differentiation of naive CD4 + precursor T cells 4 . The high efficiency with which T H 1- and T H 2-cell differentiation can be induced in vitro by IL-12 and IL-4, respectively, has led to the widespread belief that these cytokines are the main inducers of these T H -cell subsets. However, many T H 1- and T H 2-cell responses in vivo are partially or completely independent of these cytokines. Although certain T H 1-cell responses in vivo are reduced in the absence of IL-12 or of components of the IL-12 receptor (IL-12R) signalling pathway, such responses are never completely abrogated 5–8 . It has been argued that the primary function of this cytokine is not to induce T H 1-cell differentiation, but instead to select cells that are already committed to the T H 1-cell lineage and enhance their effector function 6,9,10 . For example, the number of T H 1 cells that developed following immu- nization with soluble extract from Toxoplasma gondii tachyzoites was almost as high in the absence as in the presence of IL-12, although the production of IFNγ was markedly reduced in the absence of IL-12 (REF. 9). Some T H 1-cell responses are entirely independent of IL-12, including those that cause diabetes in non-obese dia- betic mice 11 and those that are generated in response to some viruses, such as lymphocytic choriomeningitis virus and mouse hepatitis virus 12–14 . Similarly, although some T H 2-cell responses are decreased in mice that lack components of the IL-4R signalling pathway 15,16 , T H 2-cell differentiation in vivo is mostly independent of IL-4. For example, the absolute numbers of T H 2 cells that are generated following infec- tion with helminths are similar in wild-type mice and mice that are deficient for signal transducer and activa- tor of transcription 6 (STAT6; an essential transcrip- tion factor for IL-4R signalling) 9,17–20 . IL-4-independent T H 2-cell responses are also mounted to other types of antigen 17 , with the most potent inducers of T H 2-cell responses being the least dependent on IL-4. IL-4 might function mainly to amplify T H 2-cell responses and might be necessary when other signals that drive T H 2-cell differentiation are limiting. The finding that T H 1- and T H 2-cell responses can be generated in the absence of IL-12 and IL-4, respectively, suggests that there are other factors that can instruct *Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ‡ Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. § Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA. Correspondence to D.A. or R.A.F. e-mails: D.amsen@amc.uva.nl; richard.flavell@yale.edu doi:10.1038/nri2488 T H 17 cell A type of CD4 + T helper (T H ) cell that produces interleukin-17 (IL-17) and that is thought to be important in inflammatory and autoimmune diseases. The generation of T H 17 cells involves IL-6 and transforming growth factor-β, as well as the transcription factors RORgt (retinoic-acid- receptor-related orphan receptor-gt) and STAT3 (signal transducer and activator of transcription 3). The different faces of Notch in T-helper-cell differentiation Derk Amsen*, Andrey Antov ‡ and Richard A. Flavell ‡§ Abstract | Interleukin‑12 (IL‑12) and IL‑4 induce T helper 1 (T H 1)‑ and T H 2‑cell differentiation, respectively, in vitro. However, not all T H 1‑cell responses require IL‑12 in vivo, and T H 2‑cell responses are remarkably independent of IL‑4‑receptor signalling, suggesting that other polarizing signals must exist. Accumulating evidence indicates that Notch is a candidate receptor that might mediate these signals. However, contrasting roles for Notch have been proposed: some evidence shows that Notch promotes T H 1‑cell differentiation, whereas other evidence supports a prominent role for Notch in T H 2‑cell differentiation. In this Review, we discuss recent findings that help to reconcile this discrepancy and highlight the accumulating evidence for the role of Notch in T‑cell‑mediated diseases. REVIEWS 116 | FEBRUARY 2009 | VOLUME 9 www.nature.com/reviews/immunol focuS on cD4 + T-cEll DIVERSITy © 2009 Macmillan Publishers Limited. All rights reserved