SUMMARY Fetal CD4+ lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid-tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that following infection with Citrobacter rodentium, CD4+ LTi cells were a dominant source of interleukin-22 (IL-22) early during infection. Infection-induced CD4+ LTi cell responses were IL-23-dependent, and ablation of IL-23 impaired innate immunity. Further, depletion of CD4+ LTi cells abrogated infection-induced expression of IL-22 and anti-microbial peptides, resulting in exacerbated host mortality. LTi cells were also found to be essential for host protective immunity in lymphocyte-replete hosts. Collectively these data demonstrate that adult CD4+ LTi cells are a critical source of IL-22 and identify a previously unrecognized function for CD4+ LTi cells in promoting innate immunity in the intestine.

SUMMARY Interferon-γ (IFN-γ) promotes a population of T-bet+ CXCR3+ regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii a similar population emerged which limited T cell responses and were dependent on IFN-γ in the periphery but IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27−/− mice and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.

No abstract

The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit combined with gp130, a common receptor chain utilized by several cytokines, including IL-6. Interestingly, the IL-27 subunits p28 and EBI3 are not always co-expressed, suggesting that they may have unique functions. Here, we show IL-27p28, independent of EBI3 antagonized cytokine signaling through gp130 and IL-6 mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. IL-27p28 transgenic mice showed a major defect in germinal center formation and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.

Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. The IL-23/Th17 axis plays an important role in the pathogenesis of psoriasis, although the exact contributions of IL-23 and IL-17 in vivo remain unclear. K5.Stat3C transgenic mice constitutively express activated Stat3 within keratinocytes, and these animals develop skin lesions with histological and cytokine profiles similar to those of human plaque psoriasis. In this study, we characterized the effects of anti-mouse IL-17A, anti-mouse IL-12/23p40, and anti-mouse IL-23p19 Abs on the development of psoriasis-like lesions in K5.Stat3C transgenic mice. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs greatly inhibited 12-O-tetradecanoylphorbol-13-acetate–induced epidermal hyperplasia in the ears of K5.Stat3C mice, whereas the inhibitory effect of an anti–IL-17A Ab was relatively less prominent. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs markedly lowered transcript levels of Th17 cytokines (e.g., IL-17 and IL-22), β-defensins, and S100A family members in skin lesions. However, anti–IL-17A Ab treatment did not affect mRNA levels of Th17 cytokines. Crossing IL-17A–deficient mice with K5.Stat3C mice resulted in partial attenuation of 12-O-tetradecanoylphorbol-13-acetate–induced lesions, which were further attenuated by anti–IL-12/23p40 Ab treatment. FACS analysis of skin-draining lymph node cells from mice that were intradermally injected with IL-23 revealed an increase in both IL-22–producing T cells and NK-22 cells. Taken together, this system provides a useful mouse model for psoriasis and demonstrates distinct roles for IL-23 and IL-17.

Atherosclerosis is a chronic inflammatory disease that develops in response to injury to the vessel wall, and is augmented by hypercholesterolemia. To further delineate the role of the immune system and local factors in this process, we assessed the effects of the immunosuppressant sirolimus (Rapamycin, RAPAMUNE â , Wyeth, Collegeville, PA) on atherosclerosis in the apoE-deficient (apoE KO) mouse, a well-accepted model of cardiovascular disease. ApoE KO mice were fed a high fat diet and sirolimus was administered. After 12 weeks, atherosclerotic lesions and plasma lipoproteins were measured. The expression of cytokines associated with atherosclerosis was also examined. All groups demonstrated plasma total cholesterol (TC) >1100 mg/dL. Sirolimus treatment was associated with a 30% increase in LDL-cholesterol (LDLc) and a dose-dependent elevation in HDL-cholesterol (HDLc). Despite increased LDLc, aortic atherosclerosis was markedly reduced in all sirolimus-treated groups. Sirolimus treatment resulted in decreased expression of IL-12p40, IFN-g and IL-10 mRNA. In contrast, TGF-b1 was elevated. Sirolimus significantly reduced atherosclerosis in apo E-KO mice; this effect is independent of, and obviates, elevated plasma TC and LDLc. Sirolimus might therefore be of benefit on atherosclerosis in patients undergoing therapy, independent of any impact on circulating lipids.

Asthma is a common respiratory disease affecting approximately 300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation and airway hyperresponsiveness remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we utilized the TH17 cell adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by TNFα neutralization or neutrophil depletion. While decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved airway hyperresponsiveness to methacholine, and tissue inflammation remained elevated when compared to control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of TH17-related cytokines in their sputum compared to other severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, while T cell-driven airway hyperresponsiveness may be associated with tissue inflammation and other pulmonary factors.

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ER and ER . The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17 -estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ER -selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ER -selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ER agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ER -selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.