Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota–BBB communication is initiated during gestation and propagated throughout life.
Mucosal vaccination via the respiratory tract can elicit protective immunity in animal infection models, but the underlying mechanisms are still poorly understood. We show that a single intranasal application of the replication-deficient modified vaccinia virus Ankara, which is widely used as a recombinant vaccination vector, results in prominent induction of bronchus-associated lymphoid tissue (BALT). Although initial peribronchiolar infiltrations, characterized by the presence of dendritic cells (DCs) and few lymphocytes, can be found 4 d after virus application, organized lymphoid structures with segregated B and T cell zones are first observed at day 8. After intratracheal application, in vitro–differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy. Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance. Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.
The CXCR4 antagonist plerixafor augments frequency of circulating neutrophils via release from the lung and prevents neutrophil homing to the bone marrow.
Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate this type III hypersensitivity process remain poorly understood. Here, using a combination of multiphoton intravital microscopy and genomic approaches, we re-examined the cutaneous reverse passive Arthus reaction and observed that IC-activated neutrophils underwent transmigration, triggered further IC formation, and transported these ICs into the interstitium, whereas neutrophil depletion drastically reduced IC formation and ameliorated vascular leakage in vivo. Thereafter, we show that these neutrophils expressed high levels of CXCL2, which further amplified neutrophil recruitment and activation in an autocrine and/or paracrine manner. Notably, CXCL1 expression was restricted to tissue-resident cell types, but IC-activated neutrophils may also indirectly, via soluble factors, modulate macrophage CXCL1 expression. Consistent with their distinct cellular origins and localization, only neutralization of CXCL2 but not CXCL1 in the interstitium effectively reduced neutrophil recruitment. In summary, our study establishes that neutrophils are able to self-regulate their own recruitment and responses during IC-mediated inflammation through a CXCL2-driven feed forward loop.
Dendritic cells (DCs) residing in the lung are known to acquire inhaled Ag and, after migration to the draining bronchial lymph node (brLN), to present it to naive T cells in an either tolerogenic or immunogenic context. To visualize endogenous lung-derived DCs, we applied fluorescent latex beads (LXs) intratracheally, thereby in vivo labeling the majority of phagocytic cells within the lung. Of note, LX-bearing cells subsequently arriving in the draining brLN were found to represent lung-derived migratory DCs. Imaging explanted brLN by two-photon laser-scanning microscopy, we quantitatively analyzed the migration and interaction behavior of naive CD4+ T cells and endogenous, lung-derived DC presenting airway-delivered Ag under inflammatory or noninflammatory conditions. Ag-specific naive CD4+ T cells engaged in stable as well as transient contacts with LX-bearing DCs in both situations and displayed similar overall motility kinetics, including a pronounced decrease in motility at 16–20 h after antigenic challenge. In contrast, the comparative analysis of T cell–DC cluster sizes as well as contact durations strongly suggests that lung-derived migratory DCs and naive CD4+ T cells form more stable, long-lasting contacts under inflammatory conditions favoring the induction of respiratory immunity.
Basophils, a rare leukocyte population in peripheral circulation, are conventionally identified as CD45int CD49b + FcεRI + cells. Here, we show that basophils from blood and several organs of naïve wild-type mice express CD41, the α subunit of α IIb β 3 integrin. CD41 expression on basophils is upregulated after in vivo IL-3 treatment and during infection with Nippostrongylus brasiliensis (Nb). Moreover, CD41 can be used as a reliable marker for basophils, circumventing technical difficulties associated with FcεRI for basophil identification in a Nb infection model. In vitro anti-IgE cross-linking and IL-3 basophil stimulation showed that CD41 upregulation positively correlates with augmented surface expression of CD200R and increased production of IL-4/IL-13, indicating that CD41 is a basophil activation marker. Furthermore, we found that infection with Plasmodium yoelii 17X (Py17x) induced a profound basophilia and using Mcpt8 DTR reporter mice as a basophil-specific depletion model, we verified that CD41 can be used as a marker to track basophils in the steady state and during infection. During malarial infection, CD41 expression on basophils is negatively regulated by IFN-γ and positively correlates with increased basophil IL-4 production. In conclusion, we provide evidence that CD41 can be used as both an identification and activation marker for basophils during homeostasis and immune challenge.Keywords: Basophils r CD41 r Helminths r Malaria Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionType 2 immune responses, typically observed in allergic reactions, endo-and ectoparasite-mediated diseases and asthma [1][2][3][4], areCorrespondence: Dr. Nadja Bakocevic e-mail: Nadja_Bakocevic@immunol.a-star.edu.sg characterized by a complex interplay of specific cytokines such as IL-3, IL-4, IL-5, IL-13, and thymic stromal lymphopoietin [1,5], as well as the expansion of innate immune cells mainly of the eosinophil, mast cell, and basophil lineage [6][7][8][9]. Among these type 2 immune cells, basophils represent a minor subset, considered for a long time to be circulating mast cells or merely mast cell relatives [10]. However, recent evidence suggests that, as a part of Th2-type immunity, basophils have distinct effector functions C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1824 Nadja Bakocevic et al. Eur. J. Immunol. 2014. 44: 1823-1834 during endo-and ectoparasite infections [11,12]. The general confusion surrounding basophil identity arises from the multitude of similarities between basophils and mast cells. Since basophils and mast cells share overlapping functions, such as IgE-dependent degranulation and Th2-type cytokine release in vitro [13], it has been technically difficult to specifically study both cell types and dissect their roles during the course of various diseases in vivo [10]. Furthermore, both cell types share surface expression of IgE, FcεRI, and CD123 (IL-3 receptor). Discrimination is currently ba...
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