Trends in Immunology

Determining germinal centre B cell fate.

Publication Date: 2012 May 15 PMID: 22595532
Authors: Zotos, D. - Tarlinton, D. M.
Journal: Trends Immunol

The humoral immune system generates immunological memory comprising affinity matured, long-lived memory B cells and plasma cells (PCs), which are generated primarily in germinal centres (GCs). Although many factors are essential in this process, those that specifically govern B cell fate are not fully understood. The provision of T cell help to B cells is key in GC B cell fate determination, and it has become clear recently that this help involves more than direct cell-cell interactions. Recently, the cytokine interleukin (IL)-21 has been identified as a key factor that can modulate the processes within GCs and directly influence B cell fate. In this review, we examine the roles of GC cytokines in the context of cell differentiation.

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Thymic epithelial cells: working class heroes for T cell development and repertoire selection.

Publication Date: 2012 May 14 PMID: 22591984
Authors: Anderson, G. - Takahama, Y.
Journal: Trends Immunol

The thymus represents an epithelial-mesenchymal tissue, anatomically structured into discrete cortical and medullary regions that contain phenotypically and functionally distinct stromal cells, as well as thymocytes at defined stages of maturation. The stepwise progression of thymocyte development seems to require serial migration through these distinct thymic regions, where interactions with cortical thymic epithelial cell (cTEC) and medullary thymic epithelial cell (mTEC) subsets take place. Recent work on TEC subsets provides insight into T cell development and selection, such as the importance of tumour necrosis factor (TNF) receptor superfamily members in thymus medulla development, and the specialised antigen processing/presentation capacity of the thymic cortex for positive selection. Here, we summarise current knowledge on the development and function of the thymic microenvironment, paying particular attention to the cortical and medullary epithelial compartments.

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Regulation and implications of inflammatory lymphangiogenesis.

Publication Date: 2012 May 11 PMID: 22579522
Authors: Kim, H. - Kataru, R. P. - Koh, G. Y.
Journal: Trends Immunol

Lymphatic vessels (LVs) are highly dynamic structures that intimately interact with their surrounding microenvironment. They have a profound influence on the immune system and therefore can manipulate inflammatory processes. Inflammation is a major cause of adulthood lymphangiogenesis and LV remodeling. In turn, LVs can reciprocally manipulate inflammatory processes. For instance, LV growth and/or activation regulate antigen presentation and inflammatory cell recruitment to lymph nodes (LNs), and therefore critically affect adaptive immunity. The vascular endothelial growth factor (VEGF)-C-VEGF receptor-3 and VEGF-A-VEGF receptor-2 signaling pathways are particularly important in inflammatory lymphangiogenesis. LVs contribute to the pathophysiology of various inflammatory conditions. Knowledge of lymphatic biology can be applied to manipulate inflammatory disorders and divert immune responses. This review summarizes basic concepts of inflammation-relevant lymphatic biology, and describes recent progress and practical implications.

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Lymphoid microenvironments and innate lymphoid cells in the gut.

Publication Date: 2012 May 10 PMID: 22578693
Authors: Pearson, C. - Uhlig, H. H. - Powrie, F.
Journal: Trends Immunol

Gut-associated lymphoid tissue (GALT) is a sensor region for luminal content and plays an important role in lymphoid maturation, activation and differentiation. It comprises isolated and aggregated lymphoid follicles, cryptopatches (CPs) and tertiary lymphoid tissue. Innate lymphoid cells (ILCs) play a central role within GALT. Prenatal GALT development is dependent on ILC lymphoid-inducer function. Postnatally, these cells rapidly respond to commensal and pathogenic intestinal bacteria, parasites and food components by polarized cytokine production [such as interleukin (IL)-22, IL-17 or IL-13] and further contribute to GALT formation and function. Here, we discuss how ILCs shape lymphoid intestinal microenvironments and act as amplifier cells for innate and adaptive immune responses.

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How nascent phagosomes mature to become phagolysosomes.

Publication Date: 2012 May 2 PMID: 22560866
Authors: Fairn, G. D. - Grinstein, S.
Journal: Trends Immunol

Phagocytosis mediates the clearance of apoptotic bodies and also the elimination of microbial pathogens. The nascent phagocytic vacuole formed upon particle engulfment lacks microbicidal and degradative activity. These capabilities are acquired as the phagosome undergoes maturation; a progressive remodeling of its membrane and contents that culminates in the formation of phagolysosomes. Maturation entails orderly sequential fusion of the phagosomal vacuole with specialized endocytic and secretory compartments. Concomitantly, the phagosomal membrane undergoes both inward and outward vesiculation and tubulation followed by fission, thereby recycling components and maintaining its overall size. Here, we summarize what is known about the molecular machinery that governs this complex metamorphosis of phagosome maturation.

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Tuberculosis vaccine development: strength lies in tenacity.

Publication Date: 2012 May 2 PMID: 22560865
Authors: Kaufmann, S. H.
Journal: Trends Immunol

The past decade has witnessed a tremendous increase in the development of novel vaccines against tuberculosis (TB). In mice, each of these vaccine candidates stimulates an immune response that reduces the bacillary load, reflecting control but not sterilization of infection. Yet, the immune mechanisms underlying vaccine efficacy are only partially understood. In parallel to clinical assessment of current candidates, the next generation of vaccine candidates still needs to be developed. This requires basic research on how to induce the most efficacious immune response. Equally important is the dissection of immune responses in patients, latently infected healthy individuals, and participants of clinical vaccine trials. Amalgamation of this information will foster the way towards more efficacious vaccination strategies that not only prevent disease, but prevent or abolish infection.

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Toll-like receptor (TLR) and inflammasome actions in the central nervous system.

Publication Date: 2012 Apr 21 PMID: 22521509
Authors: Hanamsagar, R. - Hanke, M. L. - Kielian, T.
Journal: Trends Immunol

During the past 10 years, much attention has been focused towards elucidating the impact of Toll-like receptors (TLRs) in central nervous system (CNS) innate immunity. TLR signaling triggers the transcriptional activation of pro-interleukin-1beta (pro-IL-1beta) and pro-IL-18 that are processed into their active forms by the inflammasome. Recent studies have demonstrated inflammasome involvement during CNS infection, autoimmune disease, and injury. This review will address inflammasome actions within the CNS and how cooperation between TLR and inflammasome signaling may influence disease outcome. In addition, the concept of alternative inflammasome functions independent of IL-1 and IL-18 processing are considered in the context of CNS disease.

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CD73: a potent suppressor of antitumor immune responses.

Publication Date: 2012 May PMID: 22487321
Authors: Beavis, P. A. - Stagg, J. - Darcy, P. K. - Smyth, M. J.
Journal: Trends Immunol

Tumors use several strategies to evade immunosurveillance. One such mechanism is the generation of adenosine within the tumor microenvironment, which potently suppresses antitumor T cell responses. Adenosine within the tumor is generated by CD73, a membrane-bound nucleotidase that is expressed by tumor cells, suppressive immune subsets such as T regulatory cells (Tregs) and myeloid-derived suppressor cells and endothelial cells. Recent evidence suggests that targeted inhibition of CD73 has the potential to reduce tumorigenesis and metastasis, as well as enhancing the potency of T-cell-directed therapies. This review outlines the impact of adenosine on suppressing the antitumor response and the evidence supporting the rationale for CD73 targeting in the treatment of cancer.

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Trials and tribulations in identifying new biologic treatments for asthma.

Publication Date: 2012 May PMID: 22436378
Authors: Holgate, S. T.
Journal: Trends Immunol

Drugs used to treat asthma have a long history, beginning with the bronchodilators and evolving into compounds that suppress airway inflammation. Guidelines for treatment of asthma are largely based on disease severity and control, rather than underlying mechanisms. However, identification of biomarkers in the causal pathways of asthma is enabling responders to be differentiated from nonresponders. Initial efforts have focused on biomarkers of the T helper (Th)2 pathway because this is a target of novel therapeutics. A concerted effort is now needed to substratify asthma beyond Th2 pathways, and using appropriate biomarkers, to target only those patients likely to respond to a specific biologic. To achieve this goal, a different type of relationship is needed between academia and industry, and also within industry, to promote collaboration in the precompetitive space.

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Whole parasite vaccination approaches for prevention of malaria infection.

Publication Date: 2012 May PMID: 22405559
Authors: Butler, N. S. - Vaughan, A. M. - Harty, J. T. - Kappe, S. H.
Journal: Trends Immunol

Malaria is caused by complex protozoan Plasmodium parasites that have foiled efforts to develop a protective vaccine. Despite this, it has been known for more than 40 years that immunization with radiation-attenuated, whole Plasmodium sporozoites confers complete protection against malaria challenge. This model gave the rationale for development of recombinant and vectored subunit vaccination strategies that have, however, not yet matched whole sporozoite protective efficacy. Novel attenuation and immunization approaches for whole sporozoite vaccination and a deeper understanding of cellular and humoral protective immune responses that eliminate pre-erythrocytic stages are paving the way for the development of next-generation vaccination strategies that completely prevent malaria.

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Pathogen-specific T cell depletion and reactivation of opportunistic pathogens in HIV infection.

Publication Date: 2012 May PMID: 22398371
Authors: Geldmacher, C. - Koup, R. A.
Journal: Trends Immunol

During HIV infection, it is unclear why different opportunistic pathogens cause disease at different CD4 T cell count thresholds. Early work has shown that CD4 T cell depletion is influenced both by cellular activation status and expression of viral entry receptors. More recently, functional characteristics of the CD4 T cells, such as cytokine and chemokine production, have also been shown to influence cellular susceptibility to HIV. Here, we examine how functional differences in pathogen-specific CD4 T cells could lead to their differential loss during HIV infection. This may have implications for when different opportunistic infections occur, and a better understanding of the mechanisms for functional imprinting of antigen-specific T cells may lead to improvements in design of vaccines against HIV and opportunistic pathogens.

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Origin of blood cells and HSC production in the embryo.

Publication Date: 2012 May PMID: 22365572
Authors: Costa, G. - Kouskoff, V. - Lacaud, G.
Journal: Trends Immunol

Hematopoietic stem cells (HSCs) are capable of self-renewal and differentiation into all blood cell types. During adult life, they reside in the bone marrow in a quiescent state. By contrast, in the growing embryo hematopoiesis is sequentially found in several developmental niches. This review provides an overview of the still controversial contribution of each of these embryonic sites to the final pool of adult HSCs and discusses new insights into the cellular origin and the molecular regulation implicated in the generation of blood progenitor cells. A better understanding of HSC development during ontogeny is essential to develop new strategies to amplify HSCs or to generate them from embryonic stem cells or by somatic cell reprogramming.

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Harnessing gammadelta T cells in anticancer immunotherapy.

Publication Date: 2012 May PMID: 22364810
Authors: Hannani, D. - Ma, Y. - Yamazaki, T. - Dechanet-Merville, J. - Kroemer, G. - Zitvogel, L.
Journal: Trends Immunol

gammadelta T lymphocytes are involved in the stress response to injured epithelia and in tissue homeostasis by limiting the dissemination of malignant or infected cells and by regulating the nature of the subsequent adaptive immune response. gammadelta T cells have potent MHC-unrestricted cytotoxicity, a high potential for cytokine release and broad-spectrum recognition of cancer cells, and as such, are attractive effectors for cancer immunotherapy. Current expectations are going beyond ex vivo manipulation of the Vgamma9Vdelta2 T subset, and target novel gammadelta T cell subsets, properties or receptors, to harness these unconventional T lymphocytes against cancer. This Opinion article discusses novel aspects of gammadelta T cell function during the course of anticancer therapies, as well as new avenues for their clinical implementation.

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CD8 T cell quiescence revisited.

Publication Date: 2012 May PMID: 22361353
Authors: Hamilton, S. E. - Jameson, S. C.
Journal: Trends Immunol

Naive T cells are typically considered to be in a default state of quiescence, whereas memory T cells undergo basal proliferation and quickly exhibit effector responses when stimulated. Over the past few years, however, a more complex picture has emerged, with evidence that naive T cell quiescence is actively enforced, and that heterogeneity among naive T cells influences their capacity to escape quiescence in response to homeostatic cues. Furthermore, the active state of memory T cells may also be instructed, requiring contact with dendritic cells to avoid reversion to quiescence. Here, we discuss these new findings and propose that there is much more flexibility in the quiescent state of naive and memory T cells than previously thought.

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