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• Transcriptional control of innate lymphocyte fate decisions.

  Authors: Christoph Sn Klose, Thomas Hoyler, Elina A Kiss, Yakup Tanriver, Andreas Diefenbach

  Current opinion in immunology.

  It has recently emerged that innate lymphocytes are more diverse than previously appreciated. In addition to natural killer cells, various subsets of innate lymphoid cells are now beingIt has recently emerged that innate lymphocytes are more diverse than previously appreciated. In addition to natural killer cells, various subsets of innate lymphoid cells are now being characterized. It has become apparent that the transcriptional programs underlying lineage specification and cell fate decisions of innate lymphocytes strikingly resemble those of T cell subsets, suggesting that such transcriptional circuitry was already pre-formed in the evolutionary older innate immune system. Here, we will review recent advances in our understanding of the core transcriptional programs driving development and cell fate decisions of innate lymphocytes. We will also discuss whether these transcriptional programs are stable or flexible, thereby allowing for plastic adaptation of immune responses.

• HIV vaccine design: the neutralizing antibody conundrum.

  Authors: Leonidas Stamatatos

  Current opinion in immunology.

• Vaccines against mucosal infections.

  Authors: Jan Holmgren, Ann-Mari Svennerholm

  Current opinion in immunology.

  There remains a great need to develop vaccines against many of the pathogens that infect mucosal tissues or have a mucosal port of entry. Parenteral vaccination may protect in some instances, butThere remains a great need to develop vaccines against many of the pathogens that infect mucosal tissues or have a mucosal port of entry. Parenteral vaccination may protect in some instances, but usually a mucosal vaccination route is necessary. Mucosal vaccines also have logistic advantages over injectable vaccines by being easier to administer, having less risk of transmitting infections and potentially being easier to manufacture. Still, however, only relatively few vaccines for human use are available: oral vaccines against cholera, typhoid, polio, and rotavirus, and a nasal vaccine against influenza. For polio, typhoid and influenza, in which the pathogens reach the blood stream, there is also an injectable vaccine alternative. A problem with available oral live vaccines is their reduced immunogenicity when used in developing countries; for instance, the efficacy of rotavirus vaccines correlates closely with the national per capita income. Research is needed to define the impact of factors such as malnutrition, aberrant intestinal microflora, concomitant infections, and preexisting immunity as well as of host genetic factors on the immunogenicity of these vaccines.

• Chronic inflammation and aging: DNA damage tips the balance.

  Authors: Mary M Cavanagh, Cornelia M Weyand, Jörg J Goronzy

  Current opinion in immunology.

  The aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanismsThe aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanisms behind the amplified inflammatory profile of aged adaptive immunity, and the reciprocal relationship between chronic inflammation and immune aging. Aged hematopoietic stem cells are driven to differentiate following accumulated DNA damage, thus depleting the stem cell pool and increasing the number of damaged effector cells in the circulation. Chronic DNA damage responses in lymphocytes as well as senescent cells of other lineages initiate the production of inflammatory mediators. In addition, aged lymphocytes become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity.

• Homeostasis and function of regulatory T cells in aging.

  Authors: Jana Raynor, Celine S Lages, Hesham Shehata, David A Hildeman, Claire A Chougnet

  Current opinion in immunology.

  A hallmark of aging is the progressive deterioration of immune function. Age-related immune suppression increases susceptibility to infectious diseases and cancer, significant causes of morbidity andA hallmark of aging is the progressive deterioration of immune function. Age-related immune suppression increases susceptibility to infectious diseases and cancer, significant causes of morbidity and mortality in the elderly. In particular, age-related T cell dysfunction is a major contributor to 'immune-senescence'. Recently, it has become clear that the frequency of regulatory T cells (Treg) significantly increases in aged mice and humans. As Treg control the intensity of T cell responses, their accrual probably contributes to age-related immune dysfunction. This review will focus on mechanisms underlying Treg homeostasis and function in aging.

• Properties of end-stage human T cells defined by CD45RA re-expression.

  Authors: Sian M Henson, Natalie E Riddell, Arne N Akbar

  Current opinion in immunology.

  Persistent viral infections, inflammatory syndromes and ageing all induce the accumulation of highly differentiated CD45RA re-expressing memory T cells. These cells increase during ageing, especiallyPersistent viral infections, inflammatory syndromes and ageing all induce the accumulation of highly differentiated CD45RA re-expressing memory T cells. These cells increase during ageing, especially in individuals who are infected with cytomegalovirus (CMV). These cells have decreased proliferative capacity, increased activation of senescence signalling pathways and greater susceptibility to apoptosis in vitro. However these cells are capable of multiple effector functions and thus bear all the hallmarks of short-lived effector T cells. This indicates that senescence signalling may govern the unique characteristics of effector T cells. In this article, we address the functional and migratory properties of these T cells and mechanisms that are involved in their generation. Finally we assess the potential for manipulation of their activity and whether this may improve immune function during ageing.

• The impact of CMV infection on survival in older humans.

  Authors: Graham Pawelec, Janet E McElhaney, Allison E Aiello, Evelyna Derhovanessian

  Current opinion in immunology.

  Dysregulated immunity, 'immunosenescence', in the elderly is thought to contribute to their increased susceptibility to infectious disease and to impact on mortality. Accepted hallmarks of humanDysregulated immunity, 'immunosenescence', in the elderly is thought to contribute to their increased susceptibility to infectious disease and to impact on mortality. Accepted hallmarks of human immunosenescence are low numbers and frequencies of naïve T cells and higher numbers and frequencies of memory T cells in the peripheral blood of the elderly compared to the young. The proportion of the population infected with CMV increases with age and markedly influences these parameters. Infection with this persistent β-herpesvirus may therefore indirectly impact on survival in the elderly. Recent evidence pertaining to this controversial proposal is reviewed here.

• Recombinant bacterial vaccines.

  Authors: Meera Unnikrishnan, Rino Rappuoli, Davide Serruto

  Current opinion in immunology.

  Vaccines are currently available for many infectious diseases caused by several microbes and the prevention of disease and death by vaccination has profoundly improved public health globally.Vaccines are currently available for many infectious diseases caused by several microbes and the prevention of disease and death by vaccination has profoundly improved public health globally. However, vaccines are not yet licensed for use against many other infectious diseases and new or improved vaccines are needed to replace suboptimal vaccines, and against newly emerging pathogens. Most of the vaccines currently licensed for human use include live attenuated and inactivated or killed microorganisms. Only a small subset is based on purified components and even fewer are recombinantly produced. Novel approaches in recombinant DNA technology, genomics and structural biology have revolutionized the way vaccine candidates are developed and will make a significant impact in the generation of safer and more effective vaccines.

• Malaria vaccine development: persistent challenges.

  Authors: Ashley M Vaughan, Stefan Hi Kappe

  Current opinion in immunology.

  There is no licensed vaccine against any human parasitic disease and apicomplexan parasites cause enormous human suffering; the malaria parasite alone kills approximately one million people annuallyThere is no licensed vaccine against any human parasitic disease and apicomplexan parasites cause enormous human suffering; the malaria parasite alone kills approximately one million people annually and is the cause of the majority of infection-related deaths in the young. A malaria vaccine is essential if the goal of malaria eradication is to be achieved. Decades ago it was shown that attenuated malaria parasites could induce sterile immunity to infection but progress towards efficacious vaccines for malaria has been slow. However, recent studies have begun to tease out the immune correlates of vaccine-induced sterile protection and essential research on animal models of disease continues to guide vaccine design. Whole parasite approaches to vaccine design through attenuation as well as subunit vaccine development continue to move forward to clinical trials and are showing promising results.

• Development and function of intestinal innate lymphoid cells.

  Authors: M Cherrier, C Ohnmacht, S Cording, G Eberl

  Current opinion in immunology.

  Innate lymphoid cells (ILCs) are generated from common lymphoid precursors, like lymphocytes, but do not express an antigen receptor. ILCs include Natural Killer (NK) cells, first described 38 yearsInnate lymphoid cells (ILCs) are generated from common lymphoid precursors, like lymphocytes, but do not express an antigen receptor. ILCs include Natural Killer (NK) cells, first described 38 years ago, as well as the more recently discovered lymphoid tissue inducer (LTi) cells, NK(22) cells and ILC2s. ILCs reflect many functions of CD4(+) T helper cells by expressing IFNγ, IL-17, IL-22 or IL-13. However, in contrast to T cells, they are not selected on the basis of antigen specificity, and expand and act shortly after stimulation. Therefore, ILCs play fundamental roles early in responses to infection and injury, in the maintenance of homeostasis, and possibly in the regulation of adaptive immunity. Here, we review the recent data on the development and role of RORγt(+) ILCs and ILC2s in intestinal homeostasis and defense.

• Adjuvants for human vaccines.

  Authors: Carl R Alving, Kristina K Peachman, Mangala Rao, Steven G Reed

  Current opinion in immunology.

  Rational selection of individual adjuvants can often be made on the basis of innate molecular interactions of the foreign molecules with pattern recognition receptors such as Toll-like receptors. ForRational selection of individual adjuvants can often be made on the basis of innate molecular interactions of the foreign molecules with pattern recognition receptors such as Toll-like receptors. For example, monophosphoryl lipid A, a family of endotoxic TLR4 agonist molecules from bacteria, has recently been formulated with liposomes, oil emulsions, or aluminum salts for several vaccines. Combinations of antigens and adjuvants with particulate lipid or oil components may reveal unique properties of immune potency or efficacy, but these can sometimes be exhibited differently in rodents when compared to nonhuman primates or humans. New adjuvants, formulations, microinjection devices, and skin delivery techniques for transcutaneous immunization demonstrate that adjuvant systems can include combinations of strategies and delivery mechanisms for uniquely formulated antigens and adjuvants.

• Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung.

  Authors: Laurel A Monticelli, Gregory F Sonnenberg, David Artis

  Current opinion in immunology.

  Maintenance of epithelial barrier function in the skin, respiratory tract and intestine is critical to limit exposure to commensal and pathogenic microbes and to maintain tissue homeostasis. InnateMaintenance of epithelial barrier function in the skin, respiratory tract and intestine is critical to limit exposure to commensal and pathogenic microbes and to maintain tissue homeostasis. Innate lymphoid cells (ILCs) are a recently recognized innate immune cell population that plays critical roles in host defense, regulation of inflammation and promotion of wound healing and tissue repair at barrier surfaces. In this review we discuss recent advances in the understanding of how ILC populations in the respiratory tract impact allergic airway inflammation and lung epithelial repair.

• Vaccines for allergy.

  Authors: Birgit Linhart, Rudolf Valenta

  Current opinion in immunology.

  Vaccines aim to establish or strengthen immune responses but are also effective for the treatment of allergy. The latter is surprising because allergy represents a hyper-immune response based onVaccines aim to establish or strengthen immune responses but are also effective for the treatment of allergy. The latter is surprising because allergy represents a hyper-immune response based on immunoglobulin E production against harmless environmental antigens, i.e., allergens. Nevertheless, vaccination with allergens, termed allergen-specific immunotherapy is the only disease-modifying therapy of allergy with long-lasting effects. New forms of allergy diagnosis and allergy vaccines based on recombinant allergen-derivatives, peptides and allergen genes have emerged through molecular allergen characterization. The molecular allergy vaccines allow sophisticated targeting of the immune system and may eliminate side effects which so far have limited the use of traditional allergen extract-based vaccines. Successful clinical trials performed with the new vaccines indicate that broad allergy vaccination is on the horizon and may help to control the allergy pandemic.

• IgA synthesis: a form of functional immune adaptation extending beyond gut.

  Authors: Duncan B Sutherland, Sidonia Fagarasan

  Current opinion in immunology.

  Immunoglobulin A (IgA) is the most abundantly produced antibody isotype in mammals. The primary function of IgA is to maintain homeostasis at mucosal surfaces. IgA is generated in specialized gutImmunoglobulin A (IgA) is the most abundantly produced antibody isotype in mammals. The primary function of IgA is to maintain homeostasis at mucosal surfaces. IgA is generated in specialized gut associated lymphoid tissues (GALT) by T cell-dependent and T cell-independent mechanisms. Studies in mice have demonstrated that IgA diversification has an essential role in the regulation of gut microbiota. Aberrant bacterial growth, by activating innate and adaptive immune cells, has emerged as a risk factor for inflammatory diseases such as metabolic disorders and autoimmune diseases. Dynamic diversification of IgA shields bacterial antigens preventing inflammatory responses, but when IgA regulation is suboptimal aberrant bacterial growth and inflammation can ensue.

• Maintenance of small intestinal and colonic tolerance by IL-10-producing regulatory T cell subsets.

  Authors: Sharon Veenbergen, Janneke N Samsom

  Current opinion in immunology.

  The intestinal mucosa is continuously exposed to harmless exogenous antigens derived from food proteins and microbiota. Continuous surveillance by suppressive regulatory T cells prevents inflammatoryThe intestinal mucosa is continuously exposed to harmless exogenous antigens derived from food proteins and microbiota. Continuous surveillance by suppressive regulatory T cells prevents inflammatory responses to these antigens thereby maintaining intestinal homeostasis. The nature of the antigenic pressure varies at different locations of the intestinal tract. In agreement with this strong microenvironmental control, small intestinal and colonic regulatory T cell homeostasis varies considerably. In this review, we summarize the substantial advances that have been made in dissecting the phenotype and function of intestinal regulatory T cells, discuss how microbiota can modulate the intestinal regulatory T cell pool and review the crucial role of the immunoregulatory cytokine interleukin-10 (IL-10) in shaping and maintenance of mucosal tolerance.

• [In Process Citation].

  Authors: Anne E Corcoran, Ann J Feeney

  Current opinion in immunology. 24(2):129-31.

• Intestinal commensals: influence on immune system and tolerance to pathogens.

  Authors: Alexander V Chervonsky

  Current opinion in immunology.

  The interactions of commensal microorganisms with the host's immune system are in the spotlight. The intestinal microbiota provides both stimulatory and inhibitory signals to the host ensuring itsThe interactions of commensal microorganisms with the host's immune system are in the spotlight. The intestinal microbiota provides both stimulatory and inhibitory signals to the host ensuring its own survival and contributing to resistance to pathogens. Some microbial lineages do this better than others and are attracting a lot of attention. The microbial influences go beyond the gut and have profound effects on infections and autoimmunity in distant locations. Commensals are also involved in regulation of 'tolerance to pathogens', a fundamental type of response to infections that does not reduce pathogen burden but keeps the host healthy.

• Liberating tumor immunity.

  Authors: Linde Meyaard, Mark J Smyth

  Current opinion in immunology. 24(2):204-6.

• The role of CTCF in regulating V(D)J recombination.

  Authors: Julie Chaumeil, Jane A Skok

  Current opinion in immunology. 24(2):153-9.

  V(D)J recombination in B and T cells is required for the generation of receptors with a broad spectrum of specificity to foreign antigen. A total number of three immunoglobulin (Ig) and four T cellV(D)J recombination in B and T cells is required for the generation of receptors with a broad spectrum of specificity to foreign antigen. A total number of three immunoglobulin (Ig) and four T cell receptor (Tcr) loci can be targeted by the recombinase enzyme (RAG1/2) in a defined series of recombination events, which drive the progression of B and T cell development. This process is regulated at multiple levels to ensure lineage specific, ordered rearrangement and allelic exclusion [1]. One key component of this is modulation of chromatin looping and locus contraction, which is important in bringing widely separated gene segments into close contact with each other to enable synapse formation for lineage and stage specific V gene rearrangement [2,3,4(•),5,6(•)]. Recent studies provide new insight into looping and its role in these processes. In this review we focus on the contribution of the 11 zinc finger nuclear protein, CTCF, in mediating loop formation and conformational changes that are important for the regulation of Ig and Tcr rearrangement.

• Self-recognition and clonal selection: autoreactivity drives the generation of B cells.

  Authors: Sebastian Herzog, Hassan Jumaa

  Current opinion in immunology. 24(2):166-72.

  The diversity of B cell receptor (BCR) specificities is generated by VDJ recombination of gene segments during early B cell development, a process which bears the risk of producing BCRs thatThe diversity of B cell receptor (BCR) specificities is generated by VDJ recombination of gene segments during early B cell development, a process which bears the risk of producing BCRs that recognize and lead to the destruction of self-structures. Traditional thoughts have mainly focused on how such putatively dangerous specificities are dealt with and in how they contribute to the development of autoimmune diseases. However, a positive or even necessary role of self-recognition during B cell development has rarely been taken into account. Now, considerable data reveal that the pre-B cell receptor (pre-BCR), which marks an important checkpoint during B cell development, acts as a surrogate autoreactive receptor. This review outlines how autoreactivity is necessary for efficient B cell development and how autoreactive receptors drive positive selection, leading to a diverse repertoire of receptor specificities in the mature B cell pool.

• CD4-CD8 differentiation in the thymus: connecting circuits and building memories.

  Authors: Yumei Xiong, Rémy Bosselut

  Current opinion in immunology. 24(2):139-45.

  The proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present aThe proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present a brief overview of the transcriptional control of this process, with emphasis on two issues. The study of Cd4 expression, that had previously generated important paradigms for transcriptional regulation in eukaryotic cells, now brings new twists to the concept of 'epigenetic memory'. And connections are emerging between transcriptional regulators critical for commitment to either lineage. The present review attempts to integrate these findings and discusses the still elusive mechanisms that match CD4-CD8 lineage differentiation to MHC specificity.

• The development of LTi cells.

  Authors: Marie Cherrier, Gérard Eberl

  Current opinion in immunology. 24(2):178-83.

  Lymphoid tissue inducer (LTi) cells are programmed by the mammalian fetus to induce the development of lymph nodes and Peyer's patches. LTi cells share a pro-inflammatory profile with Th17 cells, asLymphoid tissue inducer (LTi) cells are programmed by the mammalian fetus to induce the development of lymph nodes and Peyer's patches. LTi cells share a pro-inflammatory profile with Th17 cells, as well as their requirement for the transcription factor RORγt. We discuss here the latest data on the fetal and post-natal development of LTi cells, and their relationship with the larger family of innate lymphoid cells (ILCs). We suggest that the re-programming of RORγt in a subset of common lymphoid progenitors allowed mammals to develop lymphoid organs before birth, whereas other vertebrates only develop such organs in response to infection or injury.

• The symphony of the ninth: the development and function of Th9 cells.

  Authors: Rukhsana Jabeen, Mark H Kaplan

  Current opinion in immunology.

  CD4+ T helper cells are obligate regulators of inflammatory disease. An expanding cadre of T helper (Th) subsets, specialized for promoting particular types of inflammation, function through theCD4+ T helper cells are obligate regulators of inflammatory disease. An expanding cadre of T helper (Th) subsets, specialized for promoting particular types of inflammation, function through the secretion of a restricted set of cytokines. The latest addition to the list of subsets is the Th9 cell that secretes IL-9 as a signature cytokine and contributes to several classes of inflammatory disease. In this review we focus on recent advances in understanding the development of Th9 cells, and how Th9 cells contribute to the orchestration of disease.

• The role of STAT5 in lymphocyte development and transformation.

  Authors: Lynn M Heltemes-Harris, Michael A Farrar

  Current opinion in immunology. 24(2):146-52.

  STAT5 plays a crucial role in B and T lymphocyte development. However, whether STAT5 primarily plays a role as a permissive factor, involved in lymphocyte survival, or an instructive factor, involvedSTAT5 plays a crucial role in B and T lymphocyte development. However, whether STAT5 primarily plays a role as a permissive factor, involved in lymphocyte survival, or an instructive factor, involved in lymphocyte differentiation, has been unclear. In addition, while STAT5 has been suggested to act as a transcriptional repressor, the mechanism by which it represses transcription was undefined. Recent reports have begun to shed new light on these roles for STAT5 in lymphocyte development, transcriptional repression, and leukemic transformation.

• Helper T cell diversity and plasticity.

  Authors: Shingo Nakayamada, Hayato Takahashi, Yuka Kanno, John J O'Shea

  Current opinion in immunology.

  CD4(+) helper T cells play crucial roles for host defense and immune-mediated disease by their ability to differentiate into specialized subsets. These subsets attain restricted patterns of cytokineCD4(+) helper T cells play crucial roles for host defense and immune-mediated disease by their ability to differentiate into specialized subsets. These subsets attain restricted patterns of cytokine secretion and specific expression of master transcription factors in response to microbial pathogens. Classically, the various helper CD4(+) T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, following the recognition of new subsets, there is increased recognition of plasticity. In this review, we highlight recent advances that pertain to this topic and the mechanisms that contribute to helper CD4(+) T cell differentiation and plasticity.

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