Secondary lymphoid organs are dispensable for the development of T‐cell‐mediated immunity during tuberculosis

Tuberculosis causes 2 million deaths per year, yet in most cases the immune response successfully contains the infection and prevents disease outbreak. Induced lymphoid structures associated with pulmonary granuloma are observed during tuberculosis in both humans and mice and could orchestrate host defense. To investigate whether granuloma perform lymphoid functions, mice lacking secondary lymphoid organs (SLO) were infected with Mycobacterium tuberculosis (MTB). As in WT mice, granuloma developed, exponential growth of MTB was controlled, and antigen‐specific T‐cell responses including memory T cells were generated in the absence of SLO. Moreover, adoptively transferred T cells were primed locally in lungs in a granuloma‐dependent manner. T‐cell activation was delayed in the absence of SLO, but resulted in a normal development program including protective subsets and functional recall responses that protected mice against secondary MTB infection. Our data demonstrate that protective immune responses can be generated independently of SLO during MTB infection and implicate local pulmonary T‐cell priming as a mechanism contributing to host defense.     

CD69: from activation marker to metabolic gatekeeper

CD69 is a membrane‐bound, type II C‐lectin receptor. It is a classical early marker of lymphocyte activation due to its rapid appearance on the surface of the plasma membrane after stimulation. CD69 is expressed by several subsets of tissue resident immune cells, including resident memory T (TRM) cells and gamma delta (γδ) T cells, and is therefore considered a marker of tissue retention. Recent evidence has revealed that CD69 regulates some specific functions of selected T‐cell subsets, determining the migration‐retention ratio as well as the acquisition of effector or regulatory phenotypes. Specifically, CD69 regulates the differentiation of regulatory T (Treg) cells as well as the secretion of IFN‐γ, IL‐17, and IL‐22. The identification of putative CD69 ligands, such as Galectin‐1 (Gal‐1), suggests that CD69‐induced signaling can be regulated not only during cognate contacts between T cells and antigen‐presenting cells in lymphoid organs, but also in the periphery, where cytokines and other metabolites control the final outcome of the immune response. Here, we will discuss new aspects of the molecular signaling mediated by CD69 and its involvement in the metabolic reprogramming regulating TH‐effector lineages.     

Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells

The fates of dendritic cells (DCs) after antigen presentation have been studied extensively, but the influence of lymphoid microenvironments on DCs is mostly unknown. Here, using splenic stromal cells to mimic the immune microenvironment, we show that contact with stromal cells promoted mature DCs to proliferate in a fibronectin-dependent way and that both stromal cell contact and stromal cell-derived transforming growth factor-beta induced their differentiation into a new regulatory DC subset. We have identified an in vivo counterpart in the spleen with similar phenotype and functions. These differentiated DCs secreted nitric oxide, which mediated the suppression of T cell proliferation in response to antigen presentation by mature DCs. Thus, our findings identify an important mechanism by which the microenvironment regulates immune responses.     

Fibroblastic reticular cells at the nexus of innate and adaptive immune responses

Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune‐interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat‐associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses.     

Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity

Secondary lymphoid organs (SLOs), including lymph nodes, Peyer's patches, and the spleen, have evolved to bring cells of the immune system together. In these collaborative environments, lymphocytes scan the surfaces of antigen-presenting cells for cognate antigens, while moving along stromal networks. The cell-cell interactions between stromal and hematopoietic cells in SLOs are therefore integral to the normal functioning of these tissues. Not only do stromal cells physically construct SLO architecture but they are essential for regulating hematopoietic populations within these domains. Stromal cells interact closely with lymphocytes and dendritic cells, providing scaffolds on which these cells migrate, and recruiting them into niches by secreting chemokines. Within lymph nodes, stromal cell-ensheathed conduit networks transport small antigens deep into the SLO parenchyma. More recently, stromal cells have been found to induce peripheral CD8⁺ T-cell tolerance and control the extent to which newly activated T cells proliferate within lymph nodes. Thus, stromal-hematopoietic crosstalk has important consequences for regulating immune cell function within SLOs. In addition, stromal cell interactions with hematopoietic cells, other stroma, and the inflammatory milieu have profound effects on key stromal functions. Here, we examine ways in which these interactions within the lymph node environment influence the adaptive immune response.     

Pathways of memory CD8+ T‐cell development

CD8⁺ T‐cell responses must have at least two components, a replicative cell type that proliferates in the secondary lymphoid tissue and that is responsible for clonal expansion, and cytotoxic cells with effector functions that mediate the resolution of the infection in the peripheral tissues. To confer memory, the response must also generate replication‐competent T cells that persist in the absence of antigen after the primary infection is cleared. The current models of memory differentiation differ in regards to whether or not memory CD8⁺ T cells acquire effector functions during their development. In this review we discuss the existing models for memory development and the consequences that the recent finding that memory CD8⁺ T cells may express granzyme B during their development has for them. We propose that memory CD8⁺ T cells represent a self‐renewing population of T cells that may acquire effector functions but that do not lose the naïve‐like attributes of lymphoid homing, antigen‐independent persistence or the capacity for self‐renewal.     

滤泡树突状细胞与生发中心反应研究的新进展

生发中心是在T细胞依赖性抗体应答过程中于外周淋巴组织内形成的一个特殊的结构。在GC内,受抗原刺激而活化的B细胞进行克隆扩增、IgV区基因的体细胞高度突变、亲和力成熟以及同类型转换,最终形成记忆性B细胞或是产生Ig的浆细胞。在GC内B细胞增殖的同时,也启动了凋亡机制,以确保最终形成的记忆B细胞或浆细胞对抗原的高度特异性。FDCs是参与再次免疫应答的重要细胞,它主要是通过表面的FcR和CR将免疫复合物结合在细胞膜上,并选择性的将抗原递呈给表达高亲和力BCR的B细胞,使之激活并产生抗体或形成记忆B细胞。因此,FDCs在生发中心反应、免疫记忆的维持、B细胞的分化、成熟以及记忆B细胞的形成具有极其重要的作用。但最近的研究对FDCs及其结合的免疫复合物的重要性提出了质疑,认为FDCs在生发中心反应、B细胞的分化、成熟以及记忆B细胞的形成中的作用很可能是非特异性的,并对驻留在FDCs表面的免疫复合物的其它潜在功能进行了讨论。     

Adaptive immune education by gut microbiota antigens

Host–microbiota mutualism has been established during long‐term co‐evolution. A diverse and rich gut microbiota plays an essential role in the development and maturation of the host immune system. Education of the adaptive immune compartment by gut microbiota antigens is important in establishing immune balance. In particular, a critical time frame immediately after birth provides a ‘window of opportunity’ for the development of lymphoid structures, differentiation and maturation of T and B cells and, most importantly, establishment of immune tolerance to gut commensals. Depending on the colonization niche, antigen type and metabolic property of different gut microbes, CD4 T‐cell responses vary greatly, which results in differentiation into distinct subsets. As a consequence, certain bacteria elicit effector‐like immune responses by promoting the production of pro‐inflammatory cytokines such as interferon‐γ and interleukin‐17A, whereas other bacteria favour the generation of regulatory CD4 T cells and provide help with gut homeostasis. The microbiota have profound effects on B cells also. Gut microbial exposure leads to a continuous diversification of B‐cell repertoire and the production of T‐dependent and ‐independent antibodies, especially IgA. These combined effects of the gut microbes provide an elegant educational process to the adaptive immune network. Contrariwise, failure of this process results in a reduced homeostasis with the gut microbiota, and an increased susceptibility to various immune disorders, both inside and outside the gut. With more definitive microbial–immune relations waiting to be discovered, modulation of the host gut microbiota has a promising future for disease intervention.     

B cell migration and interactions in the early phase of antibody responses

In the early phase of thymus-dependent antibody responses antigen-engaged B cells rapidly change their localization within the secondary lymphoid organs to access helper T cells. Central to this process is the tightly controlled distribution of chemokines, sphingosine-1-phosphate and other guidance cues within the lymphoid organ, determined in part by the stromal cells, and the changing responsiveness of activated lymphocytes to these cues. Studies that use the emerging technique of real-time two-photon imaging of intact lymphoid organs began to dissect the dynamics of B cell migration before and after antigen engagement in vivo. Recent studies also provided new insight into antigen transport mechanisms in lymphoid organs and examined signaling requirements for B lymphocyte positioning and motility. Taken together, these studies have provided a more detailed map of the steps involved in B cell migration to encounter antigen and helper T cells early during the adaptive immune response.     

Roles of embryonic and adult lymphoid tissue inducer cells in primary and secondary lymphoid tissues

The nomenclature "embryonic lymphoid tissue inducer (LTi) cell" reflects the fundamental role of the cell in secondary lymphoid tissue organization. In addition, it is equally important in primary lymphoid tissue development as it regulates central tolerance to self-antigens in the thymus. An adult LTi cell constitutively expresses two sets of tumor necrosis factor (TNF) family members, whereas its embryonic counterpart expresses only one. The first set is lymphotoxin (LT)alpha, LTbeta, and TNalpha, which are essential for the secondary lymphoid organogenesis during embryogenesis and for maintaining an organized secondary lymphoid structure during adulthood. The second set is OX40- and CD30-ligands, which are critical for memory T cell generation. Adult LTi cells regulate adaptive immune responses by providing LTbetaR signals to stromal cells to maintain secondary lymphoid tissue structure, and determine adaptive immune responses by providing OX40 and CD30 survival signals to activated T cells in memory T cell generation. Along with the consideration of the roles of embryonic LTi cells in primary and secondary lymphoid tissues, this review highlights the roles of adult LTi cells in secondary lymphoid tissue function.     

Understanding T cell signaling using membrane reconstitution

T cells are central players of our immune system, as their functions range from killing tumorous and virus‐infected cells to orchestrating the entire immune response. In order for T cells to divide and execute their functions, they must be activated by antigen‐presenting cells (APCs) through a cell‐cell junction. Extracellular interactions between receptors on T cells and their ligands on APCs trigger signaling cascades comprised of protein‐protein interactions, enzymatic reactions, and spatial reorganization events, to either stimulate or repress T cell activation. Plasma membrane is the major platform for T cell signaling. Recruitment of cytosolic proteins to membrane‐bound receptors is a common critical step in many signaling pathways. Membranes decrease the dimensionality of protein‐protein interactions to enable weak yet biologically important interactions. Membrane resident proteins can phase separate into micro‐islands that promote signaling by enriching or excluding signal regulators. Moreover, some membrane lipids can either mediate or regulate cell signaling by interacting with signaling proteins. While it is critical to investigate T cell signaling in a cellular environment, the large number of signaling pathways involved and potential crosstalk have made it difficult to obtain precise, quantitative information on T cell signaling. Reconstitution of purified proteins to model membranes provides a complementary avenue for T cell signaling research. Here, I review recent progress in studying T cell signaling using membrane reconstitution approaches.     

Effect of tumor cells and tumor microenvironment on NK‐cell function

The ability of tumors to manage an immune‐mediated attack has been recently included in the “next generation” of cancer hallmarks. In solid tumors, the microenvironment that is generated during the first steps of tumor development has a pivotal role in immune regulation. An intricate net of cross‐interactions occurring between tumor components, stromal cells, and resident or recruited immune cells skews the possible acute inflammatory response toward an aberrant ineffective chronic inflammatory status that favors the evasion from the host's defenses. Natural killer (NK) cells have powerful cytotoxic activity, but their activity may be eluded by the tumor microenvironment. Immunosubversion, immunoediting or immunoselection of poorly immunogenic tumor cells and interference with tumor infiltration play a major role in evading NK‐cell responses to tumors. Tumor cells, tumor‐associated fibroblasts and tumor‐induced aberrant immune cells (i.e. tolerogenic or suppressive macrophages, dendritic cells (DCs) and T cells) can interfere with NK‐cell activation pathways or the complex receptor array that regulate NK‐cell activation and antitumor activity. Thus, the definition of tumor microenvironment‐related immunosuppressive factors, along with the identification of new classes of tissue‐residing NK‐like innate lymphoid cells, represent key issues to design effective NK‐cell‐based therapies of solid tumors.     

Guidance factors orchestrating regulatory T cell positioning in tissues during development,homeostasis, and response

Over their lifetime, regulatory T cells (Treg) recalibrate their expression of trafficking receptors multiple times as they progress through development, respond to immune challenges, or adapt to the requirements of functioning in various non‐lymphoid tissue environments. These trafficking receptors, which include chemokine receptors and other G‐protein coupled receptors, integrins, as well as selectins and their ligands, enable Treg not only to enter appropriate tissues from the bloodstream via post‐capillary venules, but also to navigate these tissues to locally execute their immune‐regulatory functions, and finally to seek out the right antigen‐presenting cells and interact with these, in part in order to receive the signals that sustain their survival, proliferation, and functional activity, in part in order to execute their immuno‐regulatory function by altering antigen presenting cell function. Here, we will review our current knowledge of when and in what ways Treg alter their trafficking properties. We will focus on the chemokine system and try to identify specialized, non‐redundant roles of individual receptors as well as similarities and differences to the conventional T cell compartment.     

Phenotypic and Functional Plasticity of Gamma–Delta (γδ) T Cells in Inflammation and Tolerance

Gamma–delta T cells (γδ T cells) are an unique group of lymphocytes and play an important role in bridging the gap between innate and adaptive immune systems under homeostatic condition as well as during infection and inflammation. They are predominantly localized into the mucosal and epithelial sites, but also exist in other peripheral tissues and secondary lymphoid organs. γδ T cells can produce cytokines and chemokines to regulate the migration of other immune cells, can bring about lysis of infected or stressed cells by secreting granzymes, provide help to B cells and induce IgE production, can present antigen to conventional T cells, activate antigen presenting cells (APC) maturation, and are also known to produce growth factors that regulate the stromal cell function. γδ T cells spontaneously produce IFN-γ and IL-17 cytokines compared to delayed differentiation of Th1 and Th17 cells. In this review, we discussed the current knowledge about the mechanism of γδ T cell function including its mode of antigen recognition, and differentiation into various subsets of γδ T cells. We also explored how γδ T cells interact with different types of innate and adaptive immune cells, and how these interactions shape the immune response highlighting the plasticity and role of these cells—protective or pathogenic under inflammatory and tolerogenic conditions.     

The control of apoptosis in lymphocyte selection

Summary: The stochastic nature of rearrangement and diversification of the gene segments encoding immunoglobulins (Igs) and T cell receptors (TCRs) inevitably gives rise to immature B and T lymphocytes that lack antigen receptors or express useless or dangerous (self‐antigen‐specific) ones. Signaling through antigen receptors promotes survival, proliferative expansion and further differentiation of useful cells and deletion of the useless and dangerous ones. During immune responses, pathogen‐specific B and T lymphocytes, as well as cells of the innate immune system, undergo extensive proliferation and develop effector functions, such as antibody secretion, cytotoxicity or cytokine production. To prevent tissue damage by these effector molecules, activated lymphocytes are removed when an infection has been overcome. Together with other mechanisms, including developmental arrest and induction of unresponsiveness (anergy), programmed cell death (apoptosis) of autoreactive lymphocytes safeguards immunological tolerance to self and assists in the development of an effective immune system. We have been investigating the molecular mechanisms that control programmed cell death. This review describes some of our experiments using transgenic and knockout mice, which overexpress or lack apoptosis regulators, that led to discoveries on how life and death decisions are made during development and functioning of the immune system.     

Lymphoid stroma in the initiation and control of immune responses

Summary: The lymphoid tissues are characterized by a complex organized architecture that is supported by a network of stromal cells. These stromal cells play many important roles in addition to serving as structural support. Lymphoid stromal cells, including the specialized fibroblastic reticular cells and follicular dendritic cells, express chemokines, cytokines, adhesion molecules, as well as other factors required for the migration, homeostasis, and survival of immune cells. Studies have demonstrated the dynamic role that lymphoid stromal cells and the chemokines they produce play in directing lymphocyte migration within the spleen and lymph nodes. The stromal network may also play roles in influencing antigen presentation, via adherence of antigen-presenting cells to the network, and cell survival, via provision of survival factors such as interleukin-7. Recently, we have shown that dramatic changes in lymphoid chemokine expression occur during many immune responses. This can alter the trafficking and localization of immune cells in lymphoid organs and has many implications for the regulation and shut-down of immune responses. Here we briefly summarize the roles of stromal cells and lymphoid architecture in the control of immune responses.     

Early programming and late‐acting checkpoints governing the development of CD4 T‐cell memory

CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T‐cell generation into vaccine strategies therefore offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long‐term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin‐2, antigen and co‐stimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through ‘programming’ that occurs during initial priming, and second, through ‘checkpoints’ that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin‐2‐, antigen‐ and co‐stimulation‐dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells.     

Cross-talk between dendritic cells and natural killer cells in viral infection

Dendritic cells (DC), first characterized in 1973 by Steinman and Cohn, have been defined as the professional antigen presenting cells (APC), capable of activating na?ve T cells much more efficiently than either B cells or macrophages. DC also capture and process antigen more efficiently than other APC, and offer MHC-antigen complexes to T cells at higher densities, and in the context of larger amounts of co-stimulatory molecules (i.e. CD40, CD80 and CD86) at the T cell-DC synapse. Although historically, the principal function of DC is the priming of na?ve T cells, more recently they have also been shown to affect the functions of natural killer (NK) cells. Interactions between DC and NK cells may be critical in situations where immune surveillance requires efficient early activation of NK cells, as is the case during infections. This review aims to summarise the interactions that occur between DC and NK cells during viral infection.