Neutrophils utilize immunoglobulins (Igs) to clear antigen, but their role in Ig production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T-independent Ig responses to circulating antigen. Neutrophils colonized peri-MZ areas after post-natal mucosal colonization by microbes and enhanced their B-helper function upon receiving reprogramming signals from splenic sinusoidal endothelial cells, including interleukin 10 (IL-10). Splenic neutrophils induced Ig class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism involving the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and less preimmune Igs to T-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial Ig defense by interacting with MZ B cells.

Mononuclear phagocytes are an important component of an innate immune system perceived as a system ready to react upon encounter of pathogens.Here, we show that in response to microbial stimulation, mononuclear phagocytes residing in nonmucosal lymphoid organs of germ-free mice failed to induce expression of a set of inflammatory response genes, including those encoding the various type I interferons (IFN-I). Consequently, NK cell priming and antiviral immunity were severely compromised. Whereas pattern recognition receptor signaling and nuclear translocation of the transcription factors NF-kB and IRF3 were normal in mononuclear phagocytes of germ-free mice, binding to their respective cytokine promoters was impaired, which correlated with the absence of activating histone marks. Our data reveal a previously unrecognized role for postnatally colonizing microbiota in the introduction of chromatin level changes in the mononuclear phagocyte system, thereby poising expression of central inflammatory genes to initiate a powerful systemic immune response during viral infection.

No abstract

[5,6] and, most recently, Th9 cells producing 8]. All of these subsets differentiate from common precursor cells depending on * These authors contributed equally to this work.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3190 Hartmann Raifer et al. Eur. J. Immunol. 2012. 42: 3189-3201 the subset-driving cytokines during the first contact with the respective antigen. In this regard, IL-12 and IL-4 are considered to be the most important cytokines for generating Th1 or Th2 cells, respectively [9], while Th9 cells are raised in response to 8] and Th17 cells by 11]. Importantly, each of the Th subsets is also characterised by a lineagecharacterising transcription factor that is relevant for the generation and/or function of the respective subset. While T-bet and GATA3 characterise Th1 and Th2 cells, respectively [12,13], Th17 cells are dependent on RORγt and RORα [14,15], and Th9 cells require PU.1 and interferon regulatory factor 4 (IRF4) [16,17]. In contrast to conventional αβ T cells, γδ T cells form a TCR with γ and δ chains. These cells are part of the innate immune system, also produce cytokines such as IL-17 and IFN-γ and seem to produce these cytokines very rapidly [18]. Furthermore, unlike the relatively time-consuming processes that are necessary for Th-cell differentiation in the periphery as outlined above, γδ T cells are apparently pre-committed for cytokine production already in the thymus [19][20][21]. Within γδ T cells, IL-17 production correlates with a CCR6+ CD27 − phenotype [20,22,23] and the Vγ4 subset is particularly biased for IL-17 production [18]. Recently, a difference between αβ T cells and γδ T cells was also reported regarding the regulation of IL-17 production: the capacity to produce IL-17 directly ex vivo was strongly dependent on the NF-κB members RelA and RelB only in thymic γδ T cells but not in αβ T cells [24]. In contrast, thymic pre-commitment for IL-17-producing γδ T cells is suppressed by engagement of Skint-1, a thymic epithelial cell determinant [25]. With respect to function, IL-17-producing γδ T cells appear to form a major component of the defence against infections with bacteria such as Mycobacterium tuberculosis, Escherichia coli and pneumococci [26][27][28]. Likewise, IL-17-producing γδ T cells arise during autoimmune disorders such as rheumatoid arthritis or experimental autoimmune encephalomyelitis (EAE) [18,29,30]. We and others have studied the relevance of the interferon regulatory family of transcription factors for Th-cell differentiation. This family includes nine members (IRF1-9) in mammals that display gene homology and binding to relatively related motifs in the promoters of the genes they regulate [31]. Within interferon regulatory families, particularly IRF1, but to a lower degree also IRF2 and IRF8 are mandatory for Th1-cell differentiation [32]. In contrast, IRF4 has relatively pleiotropic roles by being absolutely required for Th2-and Th17-cell differentiation [33][34][35][36][37] and, as recently shown, for Th9-and T FH -cel...

Large numbers of microorganisms colonise the skin and mucous membranes of animals, with their highest density in the lower gastrointestinal tract. The impact of these microbes on the host can be demonstrated by comparing animals (usually mice) housed under germ‐free conditions, or colonised with different compositions of microbes. Inbreeding and embryo manipulation programs have generated a wide variety of mouse strains with a fixed germ‐line (isogenic) and hygiene comparisons robustly show remarkably strong interactions between the microbiota and the host, which can be summarised in three axioms. (I) Live microbes are largely confined to their spaces at body surfaces, provided the animal is not suffering from an infection. (II) There is promiscuous molecular exchange throughout the host and its microbiota in both directions . (III) Every host organ system is profoundly shaped by the presence of body surface microbes. It follows that one must draw a line between live microbial and host “spaces” (I) to understand the crosstalk (II and III) at this interesting interface of the host‐microbial superorganism. Of course, since microbes can adapt to very different niches, there has to be more than one line. In this issue of EMBO Reports, Johansson and colleagues have studied mucus, which is the main physical frontier for most microbes in the intestinal tract: they report how different non‐pathogenic microbiota compositions affect its permeability and the functional protection of the epithelial surface .

In the version of this article initially published, the second affiliation for Stephanie C. Ganal is missing. This author is also affiliated with the Spemann Graduate School of Biology and Medicine, Freiburg, Germany. The error has been corrected in the HTML and PDF versions of the article.Corrigendum: Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells In the version of this article initially published online, the affiliation of author Bart Vanhaesebroeck was incorrect. The correct affiliation is as follows: Center for Cell Signaling, Barts Cancer Institute, Queen Mary University of London, London, UK. The error has been corrected for the print, PDF and HTML versions of this article. Erratum: Matching cellular dimensions with molecular sizes Michael Reth Nat. Immunol. 14, 765-767 (2013)In the version of this article originally posted online, the units in the text referring to Figure 1a were incorrect. The correct unit is "μm" and the correct text is " the receptor depicted would measure about 3 μm, compared with a resting B lymphocyte, with an average diameter of about 7 μm. " The error has been corrected in this file as of 22 August 2013.Erratum: The role of the immune system in governing host-microbe interactions in the intestine In the version of this article initially published, a label was missing from Figure 2. The lymphoid structure in the large intestine should be labeled 'Isolated lymphoid follicle' . The error has been corrected in the HTML and PDF versions of the article.c o r r i g e n d a a n d e r r ata npg

During inflammation, serum amyloid A proteins transport retinol to infected tissues.