Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F–deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases.

The molecular mechanisms underlying the initiation of innate and adaptive proallergic type 2 responses are not understood. Interleukin (IL) 25, a member of the IL-17 cytokine family, was recently reported (Owyang, A.M., C. Zaph, E.H. Wilson, K.J. Guild, T. McClanahan, H.R. Miller, D.J. Cua, M. Goldschmidt, C.A. Hunter, R.A. Kastelein, and D. Artis. 2006. J. Exp. Med. 203:843–849; Fallon, P.G., S.J. Ballantyne, N.E. Mangan, J.L. Barlow, A. Dasvarma, D.R. Hewett, A. McIlgorm, H.E. Jolin, and A.N. McKenzie. 2006. J. Exp. Med. 203:1105–1116) to be important in Th2 cell–mediated immunity to parasitic infection. However, the cellular source and targets of IL-25 are not well understood. We show that mouse IL-25 is expressed by lung epithelial cells as a result of innate immune responses to allergens. Transgenic overexpression of IL-25 by these cells leads to mucus production and airway infiltration of macrophages and eosinophils, whereas blockade of IL-25 conversely reduces the airway inflammation and Th2 cytokine production in an allergen-induced asthma model. In addition, IL-25, with a receptor more highly expressed in Th2 than other effector T cells, promotes Th2 cell differentiation in an IL-4– and signal transducer and activator of transcription 6–dependent manner. During early T cell activation, IL-25 potentiates expression of the nuclear factor of activated T cells c1 and JunB transcription factors, which possibly results in increased levels of initial IL-4 production, up-regulation of GATA-3 expression, and enhanced Th2 cell differentiation. Thus, IL-25 is a critical factor regulating the initiation of innate and adaptive proallergic responses.

Interleukin (IL)-Inflammatory reactions are complex biological processes involving both innate and adaptive immune systems. Chronic inflammation is crucially regulated by CD4 ϩ T cells in many autoimmune diseases. Recent work has identified a novel subset of CD4 ϩ T cells that produce IL-17, 3 named as THIL-17, TH17, or THi cells (1). T cell differentiation into these cells is regulated by cytokines such as TGF␤, IL-6, and IL-23 (2). More and more evidence has associated these cells with normal host responses to infection and abnormal inflammatory autoimmune diseases (1).IL-17, also called IL-17A, is the founding member of a novel cytokine family-IL-17 family (1). Widely regarded as a proinflammatory cytokine, IL-17 is crucial in regulation of tissue inflammation in vivo (3). IL-17 regulates the production of cytokines (IL-6, TNF-␣, and IL-1␤), chemokines (RANTES, MCP-1, MIP-2/IL-8, MIP-3␣, and GRO␣), cell-surface markers (RANKL and ICAM-1) and proinflammatory mediators (prostaglandin E 2 , nitric oxide, and cyclooxygenase-2) (1). Moreover, IL-17 also synergizes with TNF-␣ in inflammatory regulation (4).IL-17 binds to and signals through IL-17 receptor A (IL-17RA), a member of the IL-17R family (5). Recently, it was reported that IL-17RA might form a heterodimer with IL-17RC (6). IL-17 activates NF-B and MAP kinase pathways, which results in up-regulation of IL-6 (7, 8), although other reports have suggested JAK/STAT pathway involved in IL-17 signaling (9, 10). It was shown that IL-6 induction by IL-17 in mouse embryonic fibroblasts (MEFs) is dependent on TRAF6 (8). Thus, IL-17 may signal via mechanisms similar to IL-1 and Toll-like receptors (TLRs).How IL-17R family receptors signal remain largely unknown. IL-17RA has a long cytoplasmic tail with ϳ500 amino acids with no sequence conserved in any other cytokine receptor families, suggesting that they belong to a unique cytokine receptor family. IL-17RA and TRAF6 overexpression resulted in co-immunoprecipitation of the two molecules (8). However, it is unclear whether the association is direct. A consensus TRAF6-binding motif, PXEXXZ (X, aromatic/acidic residue), is absent in IL-17RA. Notably, TLRs, IL-1 receptors, and TNF receptors all initiate their signaling via homotypic interaction with downstream adaptor proteins. Many TLRs and IL-1 receptors utilize MyD88 in their signal transduction leading to activation of TRAF6 and downstream pathways (11). Interestingly, one article recently suggested that all isoforms of IL-17 receptors contained a conserved sequence segment that shares similar residues in two out of three conserved motifs of Toll-like receptor (TIR)/IL-1R domain. A new superfamily consisting of TIR and IL-17R homology domains was thus proposed as STIR * This work was supported in part by the National Institutes of Health (to C. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

SUMMARY The coordination of nutrient and energy availability with cell growth and division is essential for proper immune cell development and function. Using a chemical mutagenesis strategy in mice, we identified a pedigree that has a complete block in B cell development at the pre-B cell stage due to a deletion in the Fnip1 gene. Enforced expression of an immunoglobulin transgene failed to rescue B cell development. Whereas essential pre-B cell signaling molecules were activated normally in Fnip1-null pre-B cells, the metabolic regulators AMPK and mTOR were dysregulated resulting in excessive cell growth and enhanced sensitivity to apoptosis in response to metabolic stress (pre-B cell receptor cross-linking, oncogene activation). These results indicate that Folliculin-interacting protein 1 (Fnip1) is vital for B cell development and metabolic homeostasis, and reveal a metabolic checkpoint which may ensure that pre-B cells have sufficient metabolic capacity to support division, while limiting lymphomagenesis caused by deregulated growth.