Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza-induced inflammation. Based on the capacity of interleukin-6 (IL-6) to govern both optimal T-cell responses and inflammatory resolution, we hypothesised that IL-6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza-infected wild-type control and IL-6-deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL-6 displayed a profound defect in their ability to mount an anti-viral T-cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro-inflammatory cytokines, IFN-α and TNF-α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL-6 in orchestrating anti-viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology. Keywords: Adaptive immunity · Heterosubtypic immunity · IL-6 · Innate immunity · Pulmonary damageAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSeasonal influenza infects 5-15% of the global population annually and results in significant morbidity and mortality [1]. Fatal infections are characterised by severe respiratory failure, which is associated with a profound early inflammatory infiltrate, lung haemorrhage and cytokine release [2][3][4]. Disease severity may Correspondence: Dr. Sarah N. Lauder e-mail: LauderSN@cf.ac.uk therefore reflect the balance between immune-mediated control of virus replication and the extent of virus-driven immunopathology. The co-ordinate activities of the innate and adaptive immune systems are likely to contribute to this balance. In order to examine this relationship, we studied the role that the cytokine, IL-6, plays in maintaining this balance. We considered this important, as IL-6 has been reported to correspond with the magnitude of strain-independent viral replication and disease severity both in animal models and in humans [5,6]. Recent data using a mouse model of influenza infection indicate that mice lacking IL-6 are less likely to survive the infection thereby implying a beneficial effect of IL-6 in controlling the infection [7].C 2013 Cardiff University. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.2614 Sarah N. Lauder et al. Eur. J. Immunol. 2013. 43: 2613-2625 The impact of IL-6 on the host respon...

Purpose: Anticancer T-cell responses can control tumors, but immunosuppressive mechanisms in vivo prevent their function. The role of regulatory T cells (Tregs) in metastatic colorectal cancer is unclear. We have previously shown depletion of Tregs enhances colorectal cancer-specific effector T-cell responses. Low-dose cyclophosphamide targets Tregs in animal models and some human studies; however, the effect of cyclophosphamide in metastatic colorectal cancer is unknown.Experimental Design: Fifty-five patients with metastatic colorectal cancer were enrolled in a phase I/II trial and randomly assigned to receive 2-week-long courses of low-dose (50 mg twice a day) cyclophosphamide or not. The absolute number, phenotype, and antitumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, as well as during 18-month follow-up.Results: Initially, cyclophosphamide reduced proliferation in all lymphocyte subsets; however, a rapid mobilization of effector T cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell, and NK-cell numbers occurred. The expansion and subsequent activation of effector T cells was focused on tumor-specific T cells, producing both granzyme B and IFNg. Cyclophosphamide-treated patients demonstrating the most enhanced IFNg þ tumor-specific T-cell responses exhibited a significant delay in tumor progression [HR ¼ 0.29; 95% confidence interval (CI), 0.12-0.69; P ¼ 0.0047), compared with nonresponders and no-treatment controls.Conclusions: Cyclophosphamide-induced Treg depletion is mirrored by a striking boost in antitumor immunity. This study provides the first direct evidence of the benefit of naturally primed T cells in patients with metastatic colorectal cancer. Our results also support the concept that nonmutated self-antigens may act as useful targets for immunotherapies.

Introduction: Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage. Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology.

Checkpoint inhibition has established immunotherapy as a major modality of cancer treatment. However, the success of cancer immunotherapy is still limited as immune regulation of tumor immunity is very complicated and mechanisms involved may also differ among cancer types. Beside checkpoints, other good candidates for immunotherapy are immunosuppressive cytokines. TGF-β is a very potent immunosuppressive cytokine involved in suppression of tumor immunity and also necessary for the function of some regulatory cells. TGF-β has three isoforms, TGF-β 1, 2 and 3. It has been demonstrated in multiple mouse tumor models that inhibition of all three isoforms of TGF-β facilitates natural tumor immunosurveillance and tumor vaccine efficacy. However, individual isoforms of TGF-β are not well studied yet. Here, by using monoclonal antibodies (mAbs) specific for TGF-β isoforms, we asked whether it is necessary to inhibit TGF-β3 to enhance tumor immunity. We found that blockade of TGF-β1 and 2 and of all isoforms provided similar effects on tumor natural immunosurveillance and therapeutic vaccine-induced tumor immunity. The protection was CD8 T cell-dependent. Blockade of TGF-β increased vaccine-induced Th1-type response measured by IFNγ production or T-bet expression in both tumor draining lymph nodes and tumors, although it did not increase tumor antigen-specific CD8 T cell numbers. Therefore, protection correlated with qualitative rather than quantitative changes in T cells. Furthermore, when combined with PD-1 blockade, blockade of TGF-β1 and 2 further increased vaccine efficacy. In conclusion, blocking TGF-β1 and 2 is sufficient to enhance tumor immunity, and it can be further enhanced with PD-1 blockade.