NATURE REVIEWS | RHEUMATOLOGY VOLUME 5 | JUNE 2009 | 325 REVIEWS Department of Internal Medicine, Faculty of Medicine, University of Florence, Italy (F. Annunziato, L. Cosmi, F. Liotta, E. Maggi, S. Romagnani). Correspondence: S. Romagnani, Department of Internal Medicine, University of Florence, Viale Morgagni 85, Firenze 50134, Italy s.romagnani@ dmi.unifi.it Type 17 T helper cells—origins, features and possible roles in rheumatic disease Francesco Annunziato, Lorenzo Cosmi, Francesco Liotta, Enrico Maggi and Sergio Romagnani Abstract | Type 17 T helper (T H 17) cells are a population of CD4 + effector T cells that are distinct from T H 1 and T H 2 cells owing to their ability to produce interleukin (IL)-17. Although T H 1 and T H 2 cells are similar in mice and humans, T H 17 cells differ in several ways. The differentiation of mouse T H 17 cells requires transforming growth factor β and IL-6, whereas human naive T cells can develop into T H 17 cells in the presence of IL-1β and IL-23 alone, transforming growth factor β having an indirect role in their development via the selective inhibition of T H 1 cell expansion. In both mice and humans, a late developmental plasticity of T H 17 cells towards the T H 1 lineage has been shown. Mainly based on mouse gene knockout studies, T H 17 lymphocytes have been found to have a pathogenic role in several autoimmune disorders; however, whether human autoimmune disorders, including rheumatoid arthritis (RA) and psoriasis, are prevalently T H 1-mediated or T H 17-mediated, is still unclear. Research suggests that both T H 1 and T H 17 cells are involved in RA pathogenesis, raising the possibility that interventions that target both the IL-23–IL-17 (T H 17) and the IL-12–interferon γ (T H 1) axes might be successful future therapeutic approaches for RA. Annunziato, F. et al. Nat. Rev. Rheumatol. 5, 325–331 (2009); published online 12 May 2009; doi:10.1038/nrrheum.2009.80 Introduction CD4 + T helper (T H ) lymphocytes represent a hetero- geneous population of cells that have an essential role in adaptive immunity. These cells include effector cells, which are devoted to protection against pathogens, and regulatory T cells (T REG cells), which protect against effector responses to autoantigens and to exogenous antigens when they become dangerous for the body. When the response of effector CD4 + T H cells to auto- antigens or exogenous antigens is exaggerated or cannot be blocked, chronic inflammation and autoimmunity can ensue. Effector CD4 + T H cells are also heterogeneous with regard to their important protective function, enabling an appropriate adaptive immune response according to the type of invading micro-organism. Over 20 years ago, two main subsets of CD4 + T H cells with different functions and patterns of cytokine secretion were iden- tified, which were named as type 1 T H (T H 1) and type 2 T H (T H 2) lymphocytes, respectively. 1,2 T H 1 cells produce high levels of interferon (IFN)-γ, and are responsible for both phagocyte activation and the production of opsonizing and complement-fixing antibodies; thus, these cells have an important role in protection against intracellular pathogens. T H 2 cells produce interleukin (IL)-4, IL-5, IL-9 and IL-13, and are mainly involved in protection against parasitic helminths. 3 In addition to their protective functions against invading pathogens, T H 1 and T H 2 cells are involved in the development of human immune disorders: T H 1 cells are involved in the pathogenesis of organ-specific autoimmune diseases, as well as other chronic inflammatory disorders, such as Crohn’s disease, sarcoidosis, and atherosclerosis; 4 and T H 2 cells are involved in allergic disorders. 3 The T H 1–T H 2 paradigm was maintained until some years ago, when a third subset of CD4 + effector T H cells, named T H 17 cells, was identified. 5,6 Mainly based on the results obtained in gene knockout mouse models and on a few findings in human diseases, T H 17 cells are now con- sidered to be the real players in the pathogenesis of auto- immune and chronic inflammatory disorders, including rheumatoid arthritis (RA), and, according to this new view, T H 1 cells seem to have a protective rather than a pathogenic role in these diseases. In this Review, we provide an update on the role of T H 17 cells, and try to establish what rheumatologists need to know about these cells so that they can avoid oversimplifications and dogmatic views in the field. We will, therefore, focus on four main areas: characteristics of T H 17 cells in terms of their origins, development, features and functions, as identified in mice; the major—and still controversial—differences between mouse and human T H 17 cells; the relationship between T H 17 and T H 1 cells and their respective roles in immunopathology; and the possible pathogenic role of T H 17 cells in human rheumato- logic disorders, and how this knowledge might be used for the development of new therapeutic approaches. Characteristics of mouse T H 17 cells Origin and development Although it has been known for over 10 years that activated CD4 + T cells produce IL-17, the existence of T H 17 cells as a distinct subset has only been recognized relatively recently. Competing interests The authors declared no competing interests. © 2009 Macmillan Publishers Limited. All rights reserved