Showing papers by "Jason G. Cyster published in 2016"
TL;DR: The hypothesis that CCR6 expression in PP B cells is necessary for their efficient switching to IgA and for production of intestinal IgA against cholera toxin and commensal bacteria is pursued.
Abstract: Immunoglobulin A (IgA) induction primarily occurs in intestinal Peyer's patches (PPs). However, the cellular interactions necessary for IgA class switching are poorly defined. Here we show that in mice, activated B cells use the chemokine receptor CCR6 to access the subepithelial dome (SED) of PPs. There, B cells undergo prolonged interactions with SED dendritic cells (DCs). PP IgA class switching requires innate lymphoid cells, which promote lymphotoxin-β receptor (LTβR)-dependent maintenance of DCs. PP DCs augment IgA production by integrin αvβ8-mediated activation of transforming growth factor-β (TGFβ). In mice where B cells cannot access the SED, IgA responses against oral antigen and gut commensals are impaired. These studies establish the PP SED as a niche supporting DC-B cell interactions needed for TGFβ activation and induction of mucosal IgA responses.
234 citations
TL;DR: It is demonstrated that distinct niches within the lymphoid organ T zone support distinct cell fate decisions, and they establish a function for dendritic-cell-derived CD25 in controlling IL-2 availability and T-cell differentiation.
Abstract: T follicular helper (Tfh) cells are a subset of T cells carrying the CD4 antigen; they are important in supporting plasma cell and germinal centre responses. The initial induction of Tfh cell properties occurs within the first few days after activation by antigen recognition on dendritic cells, although how dendritic cells promote this cell-fate decision is not fully understood. Moreover, although Tfh cells are uniquely defined by expression of the follicle-homing receptor CXCR5 (refs 1, 2), the guidance receptor promoting the earlier localization of activated T cells at the interface of the B-cell follicle and T zone has been unclear. Here we show that the G-protein-coupled receptor EBI2 (GPR183) and its ligand 7α,25-dihydroxycholesterol mediate positioning of activated CD4 T cells at the interface of the follicle and T zone. In this location they interact with activated dendritic cells and are exposed to Tfh-cell-promoting inducible co-stimulator (ICOS) ligand. Interleukin-2 (IL-2) is a cytokine that has multiple influences on T-cell fate, including negative regulation of Tfh cell differentiation. We demonstrate that activated dendritic cells in the outer T zone further augment Tfh cell differentiation by producing membrane and soluble forms of CD25, the IL-2 receptor α-chain, and quenching T-cell-derived IL-2. Mice lacking EBI2 in T cells or CD25 in dendritic cells have reduced Tfh cells and mount defective T-cell-dependent plasma cell and germinal centre responses. These findings demonstrate that distinct niches within the lymphoid organ T zone support distinct cell fate decisions, and they establish a function for dendritic-cell-derived CD25 in controlling IL-2 availability and T-cell differentiation.
217 citations
TL;DR: Current understanding of how PPs foster B‐cell encounters with antigen is reviewed, how they favor isotype switching to the secretory IgA isotype, and how their GC responses may uniquely contribute to mucosal immunity are reviewed.
Abstract: Secondary lymphoid tissues share the important function of bringing together antigens and rare antigen-specific lymphocytes to foster induction of adaptive immune responses. Peyer's patches (PPs) are unique compared to other secondary lymphoid tissues in their continual exposure to an enormous diversity of microbiome- and food-derived antigens and in the types of pathogens they encounter. Antigens are delivered to PPs by specialized microfold (M) epithelial cells and they may be captured and presented by resident dendritic cells (DCs). In accord with their state of chronic microbial antigen exposure, PPs exhibit continual germinal center (GC) activity. These GCs not only contribute to the generation of B cells and plasma cells producing somatically mutated gut antigen-specific IgA antibodies but have also been suggested to support non-specific antigen diversification of the B-cell repertoire. Here, we review current understanding of how PPs foster B-cell encounters with antigen, how they favor isotype switching to the secretory IgA isotype, and how their GC responses may uniquely contribute to mucosal immunity.
201 citations
TL;DR: It is reported that IL7RhiCcr6+ lymphocytes in mouse LNs rapidly produce IL17 upon bacterial and fungal challenge, and it is shown that these innate-like lymphocytes are mostly LN resident and Ccr6 is required for their accumulation near the SCS and for efficient IL17 induction.
Abstract: Lymph nodes (LNs) contain innate-like lymphocytes that survey the subcapsular sinus (SCS) and associated macrophages for pathogen entry. The factors promoting this surveillance behavior have not been defined. Here, we report that IL7R(hi)Ccr6(+) lymphocytes in mouse LNs rapidly produce IL17 upon bacterial and fungal challenge. We show that these innate-like lymphocytes are mostly LN resident. Ccr6 is required for their accumulation near the SCS and for efficient IL17 induction. Migration into the SCS intrinsically requires S1pr1, whereas movement from the sinus into the parenchyma involves the integrin LFA1 and its ligand ICAM1. CD169, a sialic acid-binding lectin, helps retain the cells within the sinus, preventing their loss in lymph flow. These findings establish a role for Ccr6 in augmenting innate-like lymphocyte responses to lymph-borne pathogens, and they define requirements for cell movement between parenchyma and SCS in what we speculate is a program of immune surveillance that helps achieve LN barrier immunity.
73 citations
TL;DR: The ubiquitin E3 ligase March1 controls the turnover and surface levels of peptide–MHCII in GC B cells, contributing to optimal GC responses.
Abstract: Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHCII) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHCII surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHCII-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHCII protein turnover. Fluctuations in surface MHCII levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHCII levels, whereas CD83 expression in centrocytes helped to stabilize MHCII at that stage. Defects in MHCII ubiquitination caused GC B cells to accumulate greater amounts of a specific peptide-MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.
65 citations
TL;DR: Clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin’s role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.
Abstract: Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the β2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin’s role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.
27 citations
TL;DR: Zfp335 is presented as a model for understanding how C2H2-ZF TFs may use multiple recognition motifs to control gene expression and binds DNA and drives transcription via recognition of two distinct consensus motifs by separate ZF clusters.
Abstract: The complexities of DNA recognition by transcription factors (TFs) with multiple Cys2-His2 zinc fingers (C2H2-ZFs) remain poorly studied. We previously reported a mutation (R1092W) in the C2H2-ZF TF Zfp335 that led to selective loss of binding at a subset of targets, although the basis for this effect was unclear. We show that Zfp335 binds DNA and drives transcription via recognition of two distinct consensus motifs by separate ZF clusters and identify the specific motif interaction disrupted by R1092W. Our work presents Zfp335 as a model for understanding how C2H2-ZF TFs may use multiple recognition motifs to control gene expression.
20 citations
TL;DR: Type I interferon blocks the generation of neutralizing antibodies in response to chronic infection.
Abstract: Type I interferon blocks the generation of neutralizing antibodies in response to chronic infection.
5 citations