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Highlights of the Advances in Basic Immunology in 2011

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Cellular & Molecular Immunology (2012) 9, 197–207 ß 2012 CSI and USTC. All rights reserved 1672-7681/12 $32.00 www.nature.com/cmi REVIEW Highlights of the advances in basic immunology in 2011 Juan Liu1, Shuxun Liu1 and Xuetao Cao1,2 In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells. Cellular & Molecular Immunology (2012) 9, 197–207; doi:10.1038/cmi.2012.12; published online 23 April 2012 Keywords: ILC; innate immunity; Th17 cells; TFR cells; TLR INTRODUCTION encountered antigens. T cells, because they control both the establish- The immune system, a collection of tissues, cells and molecules, has ment and regulation of adaptive immunity, have attracted special atten- evolved to recognize and eliminate invading pathogens. Broadly, the tion in recent decades. Whereas Th1 and Th2 were first described in the immune system can be divided into two categories, the innate 1980s, interest in several other T helper subsets, including regulatory T immune system and the adaptive immune system. Although it has (Treg) cells, Th17 cells, follicular T helper (TFH) cells and regulatory been known for many years that the innate immune system constitu- follicular T (TFR) cells, has emerged in the last decade because of their tes the first line of defense against pathogens, how the innate immune unique cytokine profiles, functions and disease associations.3 In com- system senses danger signals from invading pathogens and distin- parison with T cells, the function of B cells and their flexibility and guishes self from non-self was not understood until the identification elasticity in development remain more mysterious, and the further of pattern-recognition receptors (PRRs). PRRs, which are expressed investigation of these cells has the potential for fascinating discoveries. on a variety of different cell types, recognize a number of conserved In this review, we look back on the advances in basic immunological structures in pathogens, termed pathogen-associated molecular pat- research that have had the greatest impact in 2011. We include new terns (PAMPs), and activate the downstream intracellular signaling findings on pattern-recognition (special emphasis is placed on nucleic pathways that mount inflammatory responses against invading patho- acid recognition and the regulation of innate immune responses); ILC; gens at the early phase of infection.1 During the course of PRR- the developmental programs of T helper subsets including Th2, Th17, triggered innate immune responses, a number of endogenous molecules Treg, TFH and TFR cells; and T-cell homeostasis (the balance among present in normal individuals exert dialectical regulatory effects on naive, effector and memory T cells). Perspectives and the implications controlling the magnitude and duration of the inflammatory responses of these recent findings for health and diseases, with special emphasis on to avoid harmful immunopathogenesis.2 Recently, in addition to poly- their indications for possible therapeutic strategies, are discussed. morphic nuclear leukocytes, antigen-presenting cells (including dend- ritic cells (DCs), monocytes and macrophages) and conventional NUCLEIC ACID RECOGNITION natural killer (NK) cells, as well as novel cell subsets such as innate The recognition of the enormous diversity of potential invading patho- lymphoid cells (ILCs), have been identified as members of the innate gens by the innate immune system relies on the ability of the PRRs immune system. The adaptive immune response develops in high-class expressed on innate immune cells to detect the evolutionarily conserved vertebrates in the late phase of infection to eliminate pathogens that structures on microbes, termed PAMPs. The PAMP engagement of have evaded innate immunity. Adaptive immunity is characterized by PRRs causes the activation of a series of downstream signaling events the specificity of antigen recognition mediated by a broad repertoire of that ultimately leads to the expression of pro-inflammatory cytokines antigen-specific receptors and the memory responses to previously and interferons (IFNs), which together orchestrate the early innate 1National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China and 2National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China Correspondence: Dr J Liu, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China E-mail: [email protected] or Dr XT Cao, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China E-mail: [email protected] Received 10 March 2012; accepted 20 March 2012 Highlights of the advances in basic immunology in 2011 J Liu et al 198 immune response and initiate the subsequent activation and shaping of to IFN-a/b and proinflammatory cytokine production in response to adaptive immunity.4 To date, three families of PRRs, including Toll-like pathogenic RNA. receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors In addition to the identification of additional RNA sensors, (RLRs) and nucleotide-binding oligomerization domain (NOD)-like investigators also focused on the molecular mechanisms of RNA receptors (NLRs), have been identified for their indispensable role in sensing and the discrimination between host- and pathogen-derived pathogen recognition and triggering of the antipathogen immune res- RNA. RIG-I is a key innate immune PRR that initiates an antiviral ponse. Nucleic acids are recognized as the essential components of immune response upon detection of the viral RNA PAMPs. viruses that are detected by innate immune receptors.5 However, Recently, Luo et al.,16 Kowalinski et al.17 and Jiang et al.18 inde- because nucleic acids are commonly shared by the pathogen and host, pendently clarified the molecular basis for RIG-I activation by RNA the potential recognition of self nucleic acids by PRRs increases the risk by revealing the conformational switch between the inactivated and of autoimmune or auto-inflammatory diseases. Thus, the specific and activated state of RIG-I. Their work provides an insightful under- effective detection of microbial RNA and DNA is critical for an appro- standing of the molecular mechanism involved in the activation of priate innate immune response against a pathogen. RIG-I by pathogenic RNAs. Furthermore, Daffis et al.19 and Zu¨st Several transmembrane and cytosolic receptors have been identified et al.20 recently identified the critical role of ribose 29-O-methyla- for their ability to recognize multiple forms of RNA and DNA, includ- tion in the mechanism for discriminating between self and non-self ing members of the TLRs, RLRs and several DNA sensors. To date, mRNAs. The 59 cap structures of higher eukaryote mRNAs and four TLR family members, TLR3, TLR7, TLR8 and TLR9, which are many viral RNAs contain ribose 29-O-methylation; however, until localized within endolysosomal compartments, have been studied these reports, the biological role of 29-O-methylation was extensively for their role in nucleic acid recognition and type I IFN unknown. The studies demonstrated that 29-O-methylation of the induction.6 59 cap of viral RNA enabled several viruses to evade innate antiviral Because many viruses complete their entire infectious cycle in the responses in the host, which was attributed to the reduced sensitiv- cytosol, much attention has focused on discovering a mechanism ity to the antiviral effects exhibited by IFIT1 and the inhibition of for the detection of cytosolic viral RNA and DNA, which includes type I IFN induction mediated by the cytosolic RNA sensor MDA5. the identification of cytosolic PRRs, including the known RIG-I- Therefore, the studies indicate that the 29-O-methylation of cellular like receptors that recognize cytosolic RNA and an analogous family mRNAs is a molecular signature for the discrimination of self and of cytosolic DNA sensors. The recognition of nucleic acids by cyto- non-self mRNAs.21 solic PRRs activates the transcription factor IRF3 or IRF7 (IFN regulatory factor 3 or 7) signaling pathways and potently induces Recognition of cytosolic DNA the production of type I IFN. In some cases, cytosolic DNA recog- Regarding the recognition of microbial DNA, investigators previously nition also favors
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  • Enhances Th1 Immunity in Male Mice Activity Selectively Α Activated Receptor − Antagonizing Peroxisome Proliferator

    Enhances Th1 Immunity in Male Mice Activity Selectively Α Activated Receptor − Antagonizing Peroxisome Proliferator

    The Journal of Immunology Antagonizing Peroxisome Proliferator–Activated Receptor a Activity Selectively Enhances Th1 Immunity in Male Mice Monan Angela Zhang,* Jeeyoon Jennifer Ahn,* Fei Linda Zhao,* Thirumahal Selvanantham,* Thierry Mallevaey,* Nick Stock,† Lucia Correa,† Ryan Clark,† David Spaner,*,‡,x and Shannon E. Dunn*,{,‖ Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen-induced gene peroxisome proliferator–activated receptor a (PPARa) in male CD4+ T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARa inhibits Th1 responses in male mice. In this study, we found that PPARa functions within CD4+ and CD8+ T lymphocytes and NKT cells to negatively regulate IFN-g responses in male mice and identified Ifng as the gene target of PPARa repression. Treatment of male CD4+ T cells with the PPARa agonist fenofibrate induced the recruitment of PPARa and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of fenofibrate in reducing IFN-g production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPARa, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-g responses in mice during infection with the Th1-associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN-g production by NKT, CD4+, and CD8+ T cells and improved the survival of male, but not female, mice.