Search

Neutrophil recruitment from blood into tissues is a hallmark of inflammation and anti-microbial host defense. In this issue, De Giovanni et al. describe an unanticipated role for a serotonin metabolite, 5-HIAA, which is produced by activated platelets and mast cells and engages the orphan receptor, GPR35, to recruit neutrophils to inflamed tissues. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are bone marrow-derived granular lymphocytes that have a key role in immune defense against viral and bacterial infections and malignancies. NK cells are traditionally defined as cells of the innate immune response because they lack RAG recombinase-dependent clonal antigen receptors. However, evidence suggests that specific subsets of mouse NK cells can nevertheless develop long-lived and highly specific memory to a variety of antigens. Here we review published evidence of NK cell-mediated, RAG-independent adaptive immunity. We also compare and contrast candidate mechanisms for mammalian NK cell memory and antigen recognition with other examples of RAG-independent pathways that generate antigen receptor diversity in non-mammalian species and discuss NK cell memory in the context of lymphocyte evolution. [ABSTRACT FROM AUTHOR]

Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are known to enter the blood and to home back to the BM. However, whether these migratory HSPCs also follow extramedullary traffic routes is unknown. Our group has recently shown that mouse thoracic duct (TD) lymph contains clonogenic HSPCs that possess short- and long-term multilineage reconstitution capacity in primary and secondary transplantation assays. Using BM transplantation, homing experiments, and parabiotic mice, we established that TD HSPCs originate in the BM and traffic constitutively to multiple extramedullary tissues, where they reside for several days until entering draining lymphatics to return to the blood. While these migratory properties of HSPCs resemble those of lymphocytes, circulating HSPCs access different target tissues because, unlike lymphocytes, they do not require secondary lymphoid organs to recirculate. The egress of HSPCs from extramedullary tissues into lymph depends on sphingosine-1-phosphate (S1P) receptors, particularly S1P1. We have shown that under physiological conditions migratory HSPCs contribute to the continuous restoration of specialized hematopoietic cells that reside in peripheral tissues. Upon exposure to toll-like receptor (TLR) agonists, migratory HSPCs proliferate locally within extramedullary tissues and generate innate immune effector cells. Thus, HSPCs can survey peripheral organs to replenish tissue-resident hematopoietic cells and act as a source of mature leukocytes during host defense against pathogens. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) possess the unique capacity for self-renewal and differentiation into various hematopoietic cell lineages. Here we summarize the processes that underlie their mobilization and directed migration from bone marrow into peripheral tissues and back to the bone marrow compartment. We specifically focus on the potential role of hematopoietic stem and progenitor cell (HSPC) migration in vascular diseases and review data from recent studies on mice. A better understanding of the mechanisms that guide HSPCs to vascular tissues will be critical for the development of novel therapeutic strategies to prevent or reverse cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Abstract: Antibody-secreting cells (ASCs) lodging in the mucosa of the small intestine are derived from activated B cells that are thought to arise in gut-associated lymphoid tissues (GALT). Upon leaving the GALT, B cells return to the blood where they must express the gut-homing receptors α4β7 and CCR9 in order to emigrate into the small bowel. Recent evidence indicates that gut-associated dendritic cells (DCs) in GALT induce gut-homing receptors on B cells via a mechanism that depends on the vitamin A metabolite retinoic acid (RA). In addition, although ASC associated with other mucosal tissues secrete IgA in an RA-independent fashion, the presence of high levels of RA in intestine and GALT can promote B cell class switching to IgA and thus, boost the production of IgA in the intestinal mucosa. Here, we discuss the role of RA in the imprinting of gut-homing ASC and the evidence linking RA with the generation of intestinal IgA-ASCs. [Copyright &y& Elsevier]

Regulated movement of stem cells is critical for organogenesis during development and for homeostasis and repair in adulthood. Here we analyze the biological significance and molecular mechanisms underlying stem cell trafficking in the generation of the germline, and the generation and regeneration of blood and muscle. Comparison across organisms and lineages reveals remarkable conservation as well as specialization in homing and migration mechanisms used by mature leukocytes, adult and fetal stem cells, and cancer stem cells. In vivo trafficking underpins the successful therapeutic application of hematopoietic stem cells for bone-marrow transplant, and further elucidation of homing and migration pathways in other systems will enable broader application of stem cells for targeted cell therapy and drug delivery. [Copyright &y& Elsevier]

The recent application of in vivo imaging to characterize the dynamics of T-cell activation by dendritic cells (DCs) has reshaped long-held beliefs of how adaptive immune responses are initiated. However, to improve our fundamental understanding, these new observations must be synthesized with the diverse theories and paradigms in the field, many of which were established before the advent of the cutting-edge techniques in a modern immunologist''s toolbox. A number of factors have been investigated that combine to determine the ability of the DC to activate a naïve T cell: the rules that govern the ability of a T cell to find antigen-bearing DCs; the parameters that define the dose and quality of the antigenic signal; and the mechanisms used by the T cell to interpret a given antigenic signal. Considering T-cell activation to be determined by the sum of interdependent factors might allow us to integrate seemingly disparate observations and hypotheses and to formulate testable predictions for further experimentation. [Copyright &y& Elsevier]

Tissue-resident dendritic cells (DCs) that migrate from peripheral sites to lymphoid organs are essential in the initiation of adaptive immune responses and for the maintenance of peripheral tolerance, and have been extensively studied. By contrast, blood-borne DCs represent a heterogeneous population, the origin, destination and function of which are still unclear. Recent studies have shown that circulating DCs capture blood-borne antigen and transport it into the extra-vascular space of lymphoid tissues for processing and presentation. Other findings suggest that a fraction of tissue-resident DCs might enter the blood after having acquired antigen in the periphery. Together, these studies imply that circulating DCs might modulate immune responses by translocating antigenic material from its point of origin to remote target tissues. [Copyright &y& Elsevier]

Naive and effector/memory T cells have distinct repertoires of trafficking ligands and receptors that restrict their ability to interact with specialized microvessels in different anatomical compartments and, consequently, have distinct patterns of migration. Antigen-experienced lymphocytes can be further subdivided into different subsets based on their expression of characteristic sets of trafficking receptors that favor their accumulation in certain target organs, including the skin and gut. Here, we summarize recent advances that have broadened our understanding of the cellular and molecular events that induce the generation of tissue-specific effector/memory T cells and discuss how these mechanisms could be harnessed for the therapeutic manipulation of T-cell-dependent pathologies. [Copyright &y& Elsevier]

Chemokines compose a sophisticated communication system used by all our cell types, including immune cells. Chemokine messages are decoded by specific receptors that initiate signal transduction events leading to a multitude of cellular responses, leukocyte chemotaxis and adhesion in particular. Critical determinants of the in vivo activities of chemokines in the immune system include their presentation by endothelial cells and extracellular matrix molecules, as well as their cellular uptake via "silent" chemokine receptors (interceptors) leading either to their transcytosis or to degradation. These regulatory mechanisms of chemokine histotopography, as well as the promiscuous and overlapping receptor specificities of inflammation-induced chemokines, shape innate responses to infections and tissue damage. Conversely, the specific patterns of homeostatic chemokines, where each chemokine is perceived by a single receptor, are charting lymphocyte navigation routes for immune surveillance. This review presents our current understanding of the mechanisms that regulate the cellular perception and pathophysiologic meaning of chemokines. [ABSTRACT FROM AUTHOR]

Presents information on the organization and microvascular specialization of lymph nodes (LN). Functions of LN in the immune system; Architecture of LN; Determinants of lymphocyte homing.

A central feature of the immune response is the precise spatio-temporal convergence of T cells and antigen presenting cells (APC) in particular microenvironments within secondary lymphoid organs (SLO). CCR7 and its ligands CCL19 and CCL21 have been identified as the gatekeepers for both naı¨ve T lymphocytes and dendritic cells (DC) to these defined anatomical compartments. A new perception on the regulation of lymphocyte traffic in lymph nodes (LN) has come from observations that sphingosine-1-phosphate (S1P) receptor agonists affect T cell entry and exit from these organs. Recent developments in intravital microscopy (IVM) techniques reveal unexpected autonomous random motion of lymphocytes within secondary lymphoid tissues, and provoke questions about the mechanisms that guide their compartmental navigation. [Copyright &y& Elsevier]

Summary The migratory behaviour of dendritic cells (DC) is tightly linked to their differentiation state. Precursor DC constitutively repopulate normal tissues from the bloodstream, and are recruited in elevated numbers to sites of inflammation. Whilst maturing in response to antigenic stimulation, DC acquire the capability to enter lymph nodes via afferent lymphatic vessels, thus facilitating their presentation of antigen to naïve T cells. Peripheral blood monocytes constitute a second DC precursor population, which during an inflammatory response are recruited to the affected site where some differentiate into functional DC. The availability of separate DC precursor populations is thought to be significant for the character, amplification and perpetuation of the resultant immune response. In addition, the balance between steady-state trafficking of incompletely activated DC bearing self-antigens from the periphery, and the migration of fully mature DC from inflammatory sites into lymph nodes might have profound effects upon tolerance induction and activation of T cells, respectively. [ABSTRACT FROM AUTHOR]

Interactions between nociceptors and mammalian immune cells are complex; however, most promote tissue repair and homeostasis, adaptive immune responses, or Type 2 immunity and inflammation. Nociceptors inhibit histotoxic, collateral damage-causing immune responses and promote tissue repair chiefly through the secretion of the calcitonin gene-related peptide (CGRP) neuropeptide. Nociceptors promote adaptive immunity by fine-tuning dendritic cell functions, through innervation of secondary lymphoid organs, and by communicating with B lymphocytes. Nociceptors can regulate Type 2 immunity inflammation by secreting neuropeptides or glutamate. While the primary role of nociceptors is to maintain tissue homeostasis, their actions can promote pathological conditions if unchecked. Nociceptor functions are themselves modulated by immune cell actions, forming numerous feed-forward and feed-back loops. The peripheral nervous system is being increasingly recognized as a regulator of immune responses at steady-state and in response to infections, cancer, tissue injury, and other challenges. In particular, nociceptors, a population of somatosensory neurons that confer the sensation of itch or pain, can exert both pro- and anti-inflammatory effects. Developing a better understanding of nociceptors as conductors of immune responses is at the forefront of neuroimmunology research. Nociceptors have emerged as master regulators of immune responses in both homeostatic and pathologic settings; however, their seemingly contradictory effects on the functions of different immune cell subsets have been a source of confusion. Nevertheless, work by many groups in recent years has begun to identify patterns of the modalities and consequences of nociceptor-immune system communication. Here, we review recent findings of how nociceptors affect immunity and propose an integrated concept whereby nociceptors are neither inherently pro- nor anti-inflammatory. Rather, we propose that nociceptors have the role of a rheostat that, in a context-dependent manner, favors tissue homeostasis and fine-tunes immunity by preventing excessive histotoxic inflammation, promoting tissue repair, and potentiating anticipatory and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Examines the role of microvillous receptor topography in leukocyte adhesion to endothelium under flow. Microvillous presentation for contact formation; Production of transfected L1-2 cell lines expressing wild-type and chimeric receptors; Topographic distribution of transfected wild-type and chimeric receptors on L1-2 cells.

The article discusses research study done on an approach to elicit mucosal immunity. It references a study by S. I. Hammerschmidt and colleagues, published in the July 1, 2011 issue of the "Journal of Clinical Investigation." The researchers immunized mice against chicken ovalbumin by subcutaneous injection or by oral galvage of ovalbumin directly administered to the gut mucosa. The effectiveness of such an approach to elicit mucosal immunity is explained.

T cell priming by dendritic cells (DC) from gut-associated lymphoid tissues gives rise to effector cells with pronounced gut tropism. The mechanism for DC-dependent imprinting of gut specificity has remained unknown. New findings point to retinoic acid, which is uniquely produced by intestinal DC, but not by DC from other lymphoid organs (; this issue of Immunity). [Copyright &y& Elsevier]

Examines the immune system of animals retaining specific memories of antigens. Role of T lymphocyte in the maintenance of immunological memory; Process of T cell activation; Description of dendritic cells.

Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have previously shown that genetically replacing VE-cadherin with a VE-cadherin-α-catenin (VEC-αC) fusion construct—which binds constitutively to actin—obstructs junctions, and blocks leukocyte extravasation in lung, skin and postcapillary venules of cremaster muscle. However, neutrophil recruitment into the inflamed peritoneal cavity was unimpaired. Investigating reasons for this, here, we visualized neutrophil diapedesis by 3D intravital video microscopy in the cremaster muscle and omentum, the major site of neutrophil recruitment into the peritoneal cavity. We found that 80% of neutrophil-extravasation occurred through HEVs in the omentum, which was unimpaired by VEC-αC. In addition, in larger venules (60–85 µm) of both tissues, less than 15% of neutrophils extravasated transcellularly in WT mice. However, in VEC-α-C mice, transcellular diapedesis increased severalfold in the omentum, but not in the cremaster. In line with this, omental venules expressed higher levels of ICAM-1 and atypical chemokine receptor 1. Furthermore, only in the omentum, VEC-αC expression caused reduced elongation of venular endothelium in flow-direction, suggesting different biomechanical properties. Collectively, VEC-αC does not inhibit paracellular transmigration in all types of venules and can modulate the diapedesis route. [ABSTRACT FROM AUTHOR]

Opinion. Comments on the paper by F. Moazzam, F.A. DeLano et al in the May 1997 issue of the `Proceedings of the National Academy of Sciences of the United States of America,' which focused on the insufficiency of the simple dichotomy of resting versus activated to describe a neutrophil's condition. Fluid dynamics of a neutrophil's intravascular environment; Physiologic consequences of neutrophil deformability.

Leukocyte function-associated antigen 1 (LFA-1) is the most widely expressed member of the β2 integrin family of cell-cell adhesion molecules. Although LFA-1 is thought to regulate multiple aspects of T cell immunity, its role in the response of CD8+ T cells to viral infections remains unclear. Indeed, compelling clinical evidence shows that loss of LFA-1 function predisposes to infection in humans but animal models show limited to no susceptibility to infection. Here, we addressed this conundrum in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV), where CD8+ T cells are necessary and sufficient to confer protection. To this end, we followed the fate and function of wild-type and LFA-1 deficient virus-specific CD8+ T cells and assessed the effect of blocking anti-LFA-1 monoclonal antibody in the outcome of infection. Our analysis of viral clearance and T cell responses using transcriptome profiling reveals a role for LFA-1 as a gatekeeper of effector T cell survival and dysfunction that when defective can predispose to LCMV infection. [ABSTRACT FROM AUTHOR]

Background: Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19. Methods: A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak. Results: A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2. Conclusions: Prior bisphosphonate-use was associated with dramatically reduced odds of SARSCoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes. Funding: This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH). [ABSTRACT FROM AUTHOR]

Comments on research on the role of a protein kinase C (PKC) isoform during T cell polarization and locomotion, published in the June 2001 issue of 'Nature Immunology.' Induction of the PKC isoform; Association of the PKC isoform with microtubules.

Focuses on the role of memory T cells in immune response. Sites of primary immune response; Systemic immunity provided by effector and memory T cells; Critical transformation undergone by T lymphocytes.

The author reflects on the results of a study on the therapeutic effects of immunosuppressant fingolimod on patients with relapsing multiple sclerosis. He talks about studies that unveiled the role of T-cell migration between the blood and two anatomical compartments, namely, the central nervous system and the lymph nodes. Information on the natalizumab monoclonal antibody is presented.

The article discusses various reports published within the issue, including one discussing clinical trials of natalizumab on patients with multiple sclerosis, and another discussing clinical trials of natalizumab on patients with Crohn's disease.

The article discusses the migration of T cells, which are at the center of most adaptive immune responses. T cells respond to pathogens only on direct contact with pathogen-derived antigen. These cells are supposed to migrate to sites where antigen is found. Dendritic cells in secondary lymphoid organs, which accumulate and trap antigen, informs naive T-cells regarding whether antigen is present and whether it poses a threat to the body. These cells migrate preferentially to these lymphoid tissues. The migration of T cells from blood into tissues is controlled by specialized microvessels.

The nasal mucosa is often the initial site of respiratory viral infection, replication, and transmission. Understanding how infection shapes tissue-scale primary and memory responses is critical for designing mucosal therapeutics and vaccines. We generated a single-cell RNA-sequencing atlas of the murine nasal mucosa, sampling three regions during primary influenza infection and rechallenge. Compositional analysis revealed restricted infection to the respiratory mucosa with stepwise changes in immune and epithelial cell subsets and states. We identified and characterized a rare subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells, which concurrently increased with tissue-resident memory T (T RM)-like cells. Proportionality analysis, cell-cell communication inference, and microscopy underscored the CXCL16-CXCR6 axis between KNIIFE and T RM cells. Secondary influenza challenge induced accelerated and coordinated myeloid and lymphoid responses without epithelial proliferation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses. [Display omitted] • Influenza infection induces stepwise changes in nasal epithelial and immune subsets • Single-cell compositional analyses reveal coordinated changes in time and space • Cxcl16 + epithelial KNIIFE cells line the nasal floor near Cxcr6 + T RM cells • Nasal viral rechallenge induces rapid and concerted myeloid and T cell responses The nasal mucosa is a key barrier for respiratory infections, but the cellular responses therein are poorly understood. Kazer et al. generate a longitudinal tissue-scale single-cell nasal atlas during IAV infection and rechallenge, identifying unique epithelial subsets responding to infection and revealing highly coordinated myeloid and T cell responses during rechallenge. [ABSTRACT FROM AUTHOR]

Migration of hematopoietic stem cells (HSCs) is essential during embryonic development and throughout adult life. During embryogenesis, trafficking of HSCs is responsible for the sequential colonization of different hematopoietic organs by blood-producing cells. In adulthood, circulation of HSCs maintains homeostasis of the hematopoietic system and participates in innate immune responses. HSC trafficking is also crucial in clinical settings such as bone marrow (BM) and stem cell transplantation. This review provides an overview of the molecular and cellular signals that control and fine-tune trafficking of HSCs and hematopoietic progenitor cells in embryogenesis and during postnatal life. We also discuss the potential clinical utility of therapeutic approaches to modulate HSC trafficking in patients. [ABSTRACT FROM AUTHOR]

Summary: Adaptive immunity has traditionally been considered a unique feature of vertebrate physiology. Unlike innate immune responses, which remain essentially unchanged upon exposure to a recurrent challenge with the same stimulus, adaptive immune cells possess the ability to learn and remember. Thus, secondary adaptive responses to a previously encountered challenge are qualitatively and/or quantitatively distinct from those elicited by a primary encounter. Besides this capacity to acquire long-lived memory, the second cardinal feature of adaptive immunity is antigen specificity. It has been generally believed that only T and B cells can develop antigen-specific immunologic memory, because these lymphocytes uniquely express recombination-activating gene (RAG) proteins, which are necessary for somatic rearrangement of V(D)J gene segments to assemble diverse antigen-specific receptors. However, recent work has uncovered discrete subsets of murine natural killer (NK) cells capable of mediating long-lived, antigen-specific recall responses to a variety of hapten-based contact sensitizers. These NK cells appear to use distinct, RAG-independent mechanisms to generate antigen specificity. Murine NK cells have also recently been shown to develop memory upon viral infection. Here, we review recent evidence indicating that at least some NK cells are capable of mediating what appears to be adaptive immunity and discuss potential mechanisms that may contribute to RAG-independent generation of antigenic diversity and longevity. [ABSTRACT FROM AUTHOR]

Abstract: To initiate an adaptive immune response, T cells need to interact with dendritic cells (DCs), and the duration of these interactions plays an important role. In vitro and in vivo experiments have generally tried to estimate the required period of opportunity for T cell stimulation rather than the duration of individual T cell–DC interactions. Since the application of multi-photon microscopy (MPM) to living lymphoid tissues, the interactions between immune cells, as well as the duration thereof, can directly be observed in vivo. Indeed, long-lasting interactions between T cells and DCs were shown to be important for the onset of immune responses. However, because MPM imaging is typically restricted to experiments lasting 1 h, and because T cell–DC conjugates frequently move into and out of the imaged volume, it is difficult to estimate the true duration of interactions from MPM contact data. Here, we present a method to properly make such an estimate of (the average of) the distribution of contact durations. We validate the method by applying it to spatially explicit computer simulations where the true distribution of contact duration is known. Finally, we apply our analysis to a large experimental data set of T–DC contacts, and predict an average contact time of about three hours. However, we identify a mismatch between the experimental data and the model predictions, and investigate possible causes of the mismatch, including minor tissue drift during imaging experiments. We discuss in detail how future experiments can be optimized such that MPM contact data will be minimally affected by these factors. [Copyright &y& Elsevier]

Dendritic cells (DCs) are critical for adaptive immunity and tolerance. Most DCs are strategically positioned as immune sentinels poised to respond to invading pathogens in tissues throughout the body. Differentiated DCs and their precursors also circulate in blood and can get rapidly recruited to sites of challenge. Within peripheral tissues, DCs collect antigenic material and then traffic to secondary lymphoid organs, where they communicate with lymphocytes to orchestrate adaptive immune responses. Hence, the migration and accurate positioning of DCs is indispensable for immune surveillance. Here, we review the molecular traffic signals that govern the migration of DCs throughout their life cycle. [Copyright &y& Elsevier]

Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity. [ABSTRACT FROM AUTHOR]

In individuals with chronic myeloid leukemia (CML) treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft contribute to leukemic relapse, but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Here we show that CD44 expression is increased on mouse stem-progenitor cells expressing BCR-ABL and that CD44 contributes functional E-selectin ligands. In a mouse retroviral transplantation model of CML, BCR-ABL1–transduced progenitors from CD44-mutant donors are defective in homing to recipient marrow, resulting in decreased engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engraft as efficiently as do wild-type HSCs. CD44 is dispensable for induction of acute B-lymphoblastic leukemia by BCR-ABL, indicating that CD44 is specifically required on leukemic cells that initiate CML. The requirement for donor CD44 is bypassed by direct intrafemoral injection of BCR-ABL1–transduced CD44-deficient stem cells or by coexpression of human CD44. Antibody to CD44 attenuates induction of CML-like leukemia in recipients. These results show that BCR-ABL–expressing leukemic stem cells depend to a greater extent on CD44 for homing and engraftment than do normal HSCs, and argue that CD44 blockade may be beneficial in autologous transplantation in CML. [ABSTRACT FROM AUTHOR]

The burgeoning field of leukocyte trafficking has created new and exciting opportunities in the clinic. Trafficking signals are being defined that finely control the movement of distinct subsets of immune cells into and out of specific tissues. Because the accumulation of leukocytes in tissues contributes to a wide variety of diseases, these 'molecular codes' have provided new targets for inhibiting tissue-specific inflammation, which have been confirmed in the clinic. However, immune cell migration is also critically important for the delivery of protective immune responses to tissues. Thus, the challenge for the future will be to identify the trafficking molecules that will most specifically inhibit the key subsets of cells that drive disease processes without affecting the migration and function of leukocytes required for protective immunity. [ABSTRACT FROM AUTHOR]

Primary T-cell responses in lymph nodes (LNs) require contact-dependent information exchange between T cells and dendritic cells (DCs). Because lymphocytes continually enter and leave normal LNs, the resident lymphocyte pool is composed of non-synchronized cells with different dwell times that display heterogeneous behaviour in mouse LNs in vitro. Here we employ two-photon microscopy in vivo to study antigen-presenting DCs and naive T cells whose dwell time in LNs was synchronized. During the first 8?h after entering from the blood, T cells underwent multiple short encounters with DCs, progressively decreased their motility, and upregulated activation markers. During the subsequent 12?h T cells formed long-lasting stable conjugates with DCs and began to secrete interleukin-2 and interferon-?. On the second day, coinciding with the onset of proliferation, T cells resumed their rapid migration and short DC contacts. Thus, T-cell priming by DCs occurs in three successive stages: transient serial encounters during the first activation phase are followed by a second phase of stable contacts culminating in cytokine production, which makes a transition into a third phase of high motility and rapid proliferation. [ABSTRACT FROM AUTHOR]

Discusses studies that examined the traffic signals for naïve T cell homing to secondary lymphoid organs and the factors that influence the differentiation of naïve CD8 T cells into cytotoxic and memory cells. Tools for studying T cell migration in vivo; Differentiation and migration of effector and memory CD8 T cells; Discussion on the trafficking of antigen-experienced T cells in vivo.

Immunization generates several memory T cell subsets that differ in their migratory properties, anatomic distribution, and, hence, accessibility to investigation. In this issue, Steinert et al. demonstrate that what was believed to be a minor memory cell subset in peripheral tissues has been dramatically underestimated. Thus, current models of protective immunity require revision. [ABSTRACT FROM AUTHOR]

The mesenteric lymph nodes (MLN) are a key site for the generation of adaptive immune responses to gut-derived antigenic material and immune cells within the MLN contribute to the pathophysiology of a range of conditions including inflammatory and autoimmune diseases, viral infections, graft versus host disease and cancer. Targeting immunomodulating drugs to the MLN may thus be beneficial in a range of conditions. This paper investigates the potential benefit of targeting a model immunosuppressant drug, mycophenolic acid (MPA), to T cells in the MLN, using a triglyceride (TG) mimetic prodrug approach. We confirmed that administration of MPA in the TG prodrug form (MPA-TG), increased lymphatic transport of MPA-related species 83-fold and increased MLN concentrations of MPA >20 fold, when compared to MPA alone, for up to 4 h in mice. At the same time, the plasma exposure of MPA and MPA-TG was similar, limiting the opportunity for systemic side effects. Confocal microscopy and flow cytometry studies with a fluorescent model prodrug (Bodipy-TG) revealed that the prodrug accumulated in the MLN cortex and paracortex at 5 and 10 h following administration and was highly associated with B cells and T cells that are found in these regions of the MLN. Finally, we demonstrated that MPA-TG was significantly more effective than MPA at inhibiting CD4+ and CD8+ T cell proliferation in the MLN of mice in response to an oral ovalbumin antigen challenge. In contrast, MPA-TG was no more effective than MPA at inhibiting T cell proliferation in peripheral LN when mice were challenged via SC administration of ovalbumin. This paper provides the first evidence of an in vivo pharmacodynamic benefit of targeting the MLN using a TG mimetic prodrug approach. The TG mimetic prodrug technology has the potential to benefit the treatment of a range of conditions where aberrant immune responses are initiated in gut-associated lymphoid tissues. [Display omitted] • Targeting lymphocytes in the mesenteric lymph nodes (MLN) enhances immunomodulation. • An oral triglyceride based prodrug promoted lymphatic transport and MLN targeting. • The prodrug also enhanced drug exposure to MLN lymphocytes. • A prodrug of mycophenolic acid suppressed lymphocyte proliferation in antigen challenge studies. • Triglyceride-based prodrugs may provide a means to enhance intestinal immunomodulation. [ABSTRACT FROM AUTHOR]

Understanding the ontogeny of distinct hematopoietic cell types remains a challenge. In this issue, Schraml et al. contribute to unraveling the complexity of a central component of the mononuclear phagocyte system by using a new in vivo approach to trace the progeny of common dendritic cell precursors. [ABSTRACT FROM AUTHOR]

How is the amoeboid movement of lymphocytes in secondary lymphoid organs orchestrated? In this issue of Immunity, demonstrate that stromal cell networks serve as guidance structures that direct and limit the migration of B and T cells in lymph nodes. [Copyright &y& Elsevier]

The targeted delivery of therapeutic drugs to lymph nodes (LNs) provides an unprecedented opportunity to improve the outcomes of transplantation and immune-mediated diseases. The high endothelial venule is a specialized segment of LN vasculature that uniquely expresses peripheral node addressin (PNAd) molecules. PNAd is recognized by MECA79 mAb. We previously generated a MECA79 mAb-coated microparticle (MP) that carries tacrolimus. Although this MP trafficked to LNs, it demonstrated limited therapeutic efficacy in our transplant model. Here, we have synthesized a nanoparticle (NP) as a carrier of anti-CD3, and optimized the conjugation strategy to coat the NP surface with MECA79 mAb (MECA79-anti-CD3-NP) to enhance LN accumulation. As compared with nonconjugated NPs, a significantly higher quantity of MECA79-NPs accumulated in the draining lymph node (DLN). Many MECA79-NPs underwent internalization by T cells and dendritic cells within the LNs. Short-term treatment of murine cardiac allograft recipients with MECA79-anti-CD3-NP resulted in significantly prolonged allograft survival in comparison with the control groups. Prolonged graft survival following treatment with MECA79-anti-CD3-NP was characterized by a significant increase in intragraft and DLN Treg populations. Treg depletion abrogated the prolongation of heart allograft survival. We believe this targeted approach of drug delivery could redefine the methods of administering immune therapeutics in transplantation. [ABSTRACT FROM AUTHOR]

Background: Intravascular leukocyte recruitment in most vertebrate tissues is restricted to postcapillary and collecting venules, whereas capillaries and arterioles usually support little or no leukocyte adhesion. This segmental restriction is thought to be mediated by endothelial, rather than hemodynamic, differences. The underlying mechanisms are largely unknown, in part because effective tools to distinguish, isolate, and analyze venular endothelial cells (V-ECs) and non-venular endothelial cells (NV-ECs) have been unavailable. We hypothesized that the atypical chemokine receptor DARC (Duffy Antigen Receptor for Chemokines, a.k.a. ACKR1 or CD234) may distinguish V-ECs versus NV-ECs in mice. Methods: We generated a rat-anti-mouse monoclonal antibody (MAb) that specifically recognizes the erythroid and endothelial forms of native, surface-expressed DARC. Using this reagent, we characterized DARC expression and distribution in the microvasculature of murine tissues. Results: DARC was exquisitely restricted to post-capillary and small collecting venules and completely absent from arteries, arterioles, capillaries, veins, and most lymphatics in every tissue analyzed. Accordingly, intravital microscopy showed that adhesive leukocyte-endothelial interactions were restricted to DARC+ venules. DARC was detectable over the entire circumference of V-ECs, but was more concentrated at cell-cell junctions. Analysis of single-cell suspensions suggested that the frequency of V-ECs among the total microvascular EC pool varies considerably between different tissues. Conclusions: Immunostaining of endothelial DARC allows the identification and isolation of intact V-ECs from multiple murine tissues. This strategy may be useful to dissect the mechanisms underlying segmental microvascular specialization in healthy and diseased tissues and to characterize the role of EC subsets in tissue-homeostasis, immune surveillance, infection, inflammation, and malignancies. [ABSTRACT FROM AUTHOR]

The article discusses the growing evidence that neuroimmune interactions regulate immune and inflammatory responses, specifically the communication framework between nociceptors, and dendritic cells (DCs), which orchestrate local inflammatory responses and control adaptive immunity. It mentions that the study identified three molecularly distinct modalities of communication used by nociceptors to control DC functions in a context-dependent manner chemokine production, and neuropeptide release.

Summary Infections induce pathogen-specific T cell differentiation into diverse effectors (Teff) that give rise to memory (Tmem) subsets. The cell-fate decisions and lineage relationships that underlie these transitions are poorly understood. Here, we found that the chemokine receptor CX3CR1 identifies three distinct CD8 + Teff and Tmem subsets. Classical central (Tcm) and effector memory (Tem) cells and their corresponding Teff precursors were CX3CR1 – and CX3CR1 high , respectively. Viral infection also induced a numerically stable CX3CR1 int subset that represented ∼15% of blood-borne Tmem cells. CX3CR1 int Tmem cells underwent more frequent homeostatic divisions than other Tmem subsets and not only self-renewed, but also contributed to the expanding CX3CR1 – Tcm pool. Both Tcm and CX3CR1 int cells homed to lymph nodes, but CX3CR1 int cells, and not Tem cells, predominantly surveyed peripheral tissues. As CX3CR1 int Tmem cells present unique phenotypic, homeostatic, and migratory properties, we designate this subset peripheral memory (tpm) cells and propose that tpm cells are chiefly responsible for the global surveillance of non-lymphoid tissues. [ABSTRACT FROM AUTHOR]

Heterogeneity and functional specialization among skin-resident macrophages are incompletely understood. In this study, we describe a novel subset of murine dermal perivascular macrophages that extend protrusions across the endothelial junctions in steady-state and capture blood-borne macromolecules. Unlike other skin-resident macrophages that are reconstituted by bone marrow-derived progenitors after a genotoxic insult, these cells are replenished by an extramedullary radio-resistant and UV-sensitive Bmi1+ progenitor. Furthermore, they possess a distinctive anti-inflammatory transcriptional profile, which cannot be polarized under inflammatory conditions, and are involved in repair and remodeling functions for which other skin-resident macrophages appear dispensable. Based on all their properties, we define these macrophages as Skin Transendothelial Radio-resistant Anti-inflammatory Macrophages (STREAM) and postulate that their preservation is important for skin homeostasis. [ABSTRACT FROM AUTHOR]

Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body.We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169+ macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans.The CD169+ macrophage layer physically blocks tEVdissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169+ macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity. [ABSTRACT FROM AUTHOR]

The nervous system and the immune system are the principal sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to varied stimuli, and have the capacity to form memories of these encounters leading to learned or ‘adaptive’ future responses. We review current understanding of the cross-regulation between these systems. The autonomic and somatosensory nervous systems regulate both the development and deployment of immune cells, with broad functions that impact on hematopoiesis as well as on priming, migration, and cytokine production. In turn, specific immune cell subsets contribute to homeostatic neural circuits such as those controlling metabolism, hypertension, and the inflammatory reflex. We examine the contribution of the somatosensory system to autoimmune, autoinflammatory, allergic, and infectious processes in barrier tissues and, in this context, discuss opportunities for therapeutic manipulation of neuro-immune interactions. [ABSTRACT FROM AUTHOR]

The cornea is the shield to the foreign world and thus, a primary site for peripheral infections. However, transparency and vision are incompatible with inflammation and scarring that may result from infections. Thus, the cornea is required to perform a delicate balance between fighting infections and preserving vision. To date, little is known about the specific role of antigen-presenting cells in viral keratitis. In this study, utilizing an established murine model of primary acute herpes simplex virus (HSV)-1 keratitis, we demonstrate that primary HSV keratitis results in increased conventional dendritic cells (cDCs) and macrophages within 24 hours after infection. Local depletion of cDCs in CD11c-DTR mice by subconjuntival diphtheria toxin injections, led to increased viral proliferation, and influx of inflammatory cells, resulting in increased scarring and clinical keratitis. In addition, while HSV infection resulted in significant corneal nerve destruction, local depletion of cDCs resulted in a much more severe loss of corneal nerves. Further, local cDC depletion resulted in decreased corneal nerve infection, and subsequently decreased and delayed systemic viral transmission in the trigeminal ganglion and draining lymph node, resulting in decreased mortality of mice. In contrast, sham depletion or depletion of macrophages through local injection of clodronate liposomes had neither a significant impact on the cornea, nor an effect on systemic viral transmission. In conclusion, we demonstrate that corneal cDCs may play a primary role in local corneal defense during viral keratitis and preserve vision, at the cost of inducing systemic viral dissemination, leading to increased mortality. [ABSTRACT FROM AUTHOR]