970 research outputs found
GPR35 and mediators from platelets and mast cells in neutrophil migration and inflammation.
No full textNeutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands. To place the functions of 5-HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5-HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5-HIAA-GPR35 function, and we speculate about broader influences of the GPR35 ligand-receptor system in immunity and disease
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EBI2 positions naïve and activated B cells
No full textThe immune system is organized to allow lymphocytes to survey for antigen and rapidly respond to an infection. B lymphocytes reside in B cell follicles and, upon exposure to antigen, rapidly migrate to interact with T cells, and then later go on to quickly produce protective antibodies and more slowly generate a memory response to prevent later reinfection. The role of chemokines and their receptors in positioning naïve and activated cells is well appreciated; CXCR5 is required for B cells to home to B cell follicles, and CCR7 is required for migration toward T cells. However, the positioning of B cells is not completely explained by these two chemokine receptors. During activation, B cells migrate after T cell interaction to the outer follicle, and some then migrate toward the center of the follicle to form germinal centers. The cues positioning cells to these areas have been poorly understood. Here we describe the role of the G protein coupled receptor EBI2 in positioning B cells, both homeostatically and upon activation. EBI2 promotes naïve B cell localization to the outer follicle, and EBI2 deficient cells are found toward the center of the follicle in competition. EBI2 expression is increased after B cell activation, directing activated cells to the outer follicle before CCR7 brings them toward T cells. After receiving CD40 stimulation from T cells, activated B cells migrate again to the outer follicle in an EBI2-dependent manner. EBI2 downregulation is required for B cells to move into the follicle and for germinal center development. Some cells remain at the outer follicle and produce antibody. EBI2 is required for efficient antibody production in a T-dependent immune response. These data demonstrate that EBI2 acts in coordination with the chemokine receptors CXCR5 and CCR7 to position naïve and activated B cells and contributes to the immune response
G-Protein Coupled Receptor 18 Contributes to Establishment of the CD8 Effector T Cell Compartment
No full textThe requirements for effector and memory CD8 T cell development are incompletely understood. Recent work has revealed a role for G-protein coupled receptor 18 (GPR18) in establishment of the intestinal CD8αα intraepithelial lymphocyte compartment. Here, we report that GPR18 is also functionally expressed in conventional CD8αβ T cells. When the receptor is lacking, mice develop fewer CD8+ KLRG1+ Granzyme B+ effector-memory cells. Bone marrow chimera studies show that the GPR18 requirement is CD8 T cell intrinsic. GPR18 is not required for T-bet expression in KLRG1+ CD8 T cells. Gene transduction experiments confirm the functional activity of GPR18 in CD8 T cells. In summary, we describe a novel GPCR requirement for establishment or maintenance of the CD8 KLRG1+ effector-memory T cell compartment. These findings have implications for methods to augment CD8 effector cell numbers
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The Regulation and Mechanism of Lymphocyte Egress
No full textLymphocyte and thymocyte egress are poorly understood processes that are required for proper immune function. In the periphery, naïve lymphocytes must egress from secondary lymphoid organs to recirculate and travel to other tissues. From the thymus, mature thymocytes must egress to populate the T cell compartment that surveys the periphery. The G-protein coupled receptor (GPCR) sphingosine-1-phosphate receptor-1 (S1P1) is intrinsically required for both egress steps, but how S1P1 promotes egress remains unclear.First, we studied the role of the early activation antigen CD69 during lymph node "shutdown," a transient block in lymphocyte egress triggered by various innate immune stimuli, including type I interferons (IFN-α/β). We found that CD69 interacts with and negatively regulates S1P1, acting downstream of IFN-α/β to promote lymphocyte retention in lymphoid organs. Our study is the first to describe a trafficking function for CD69 and to report an interaction between a C-type lectin and a GPCR. Next, we studied a spontaneous thymic egress mutant strain carrying the recessive ptcd (peripheral T cell deficiency) locus. We found that ptcd mice have an intrinsic T cell migration and trafficking defect, and carry a point mutation in the actin regulator Coronin-1A. This mutation causes protein mislocalization and enhanced Arp2/3 inhibition. Our findings contributed new insight to the mechanism of Arp2/3 regulation by Coronin-1A during T cell trafficking, and also prompted us to identify an atypical human T-B+NK+ SCID patient with Coronin-1A deficiency.Together, these studies contribute to our understanding of the regulation and mechanism of lymphocyte egress. Furthermore, we've provided a mechanism for the lymph node shutdown phenomenon, discovered a novel lectin-GPCR interaction, provided new insight into actin biology, and reported a novel genetic defect in a patient with T-B+NK+ severe combined immunodeficiency
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Characterization of the mechanism for lymphocyte egress from secondary lymphoid organs
No full textLymphocyte egress from peripheral lymphoid organs during recirculation is essential for normal immune functions, but the mechanisms regulating this process are still incompletely understood. From the lymph nodes, naïve lymphocytes egress into the lymph in a process that requires lymphocyte-intrinsic expression of the sphingosine-1-phosphate receptor (S1P1), a G-protein coupled receptor (GPCR). Furthermore, lymphocyte egress is dependent on a radiation resistant source that maintains the level of S1P1's ligand, sphingosine-1-phosphate (S1P), in the lymph. The cellular source of lymph S1P and how S1P1 acts to promote egress are not defined. We investigated the hypothesis that lymphocyte S1P1 functions to overcome signals that retain cells in lymphoid tissues. We found that CCR7-deficient T cells exited lymph nodes more rapidly while CCR7 overexpressing cells were retained longer, as compared to wild-type cells. Using the immunosuppressive drug FTY720 to down-modulate S1P1 function, we showed that the requirement of lymphocyte S1P1 for egress was partially relieved by CCR7 deficiency, and more fully relieved by pertussis toxin treatment (PTX) that inactivates lymphocyte Gi. PTX treatment also restored egress competence in S1P1-deficient T cells. Furthermore, we found T cell accumulation in the LYVE-1+ cortical sinuses was promoted by S1P1 and antagonized by CCR7 expression intrinsically within the lymphocytes.Next, we studied the role of lymphatic endothelial cells in generating lymph S1P. We showed that mice with tissue-specific deletion of Sphk1 by Cre expression from the lymphatic vascular endothelium gene-1 (Lyve-1) and lacking Sphk2 had a loss of S1P in the lymph while maintaining normal plasma S1P level. In lymphatic Sphk-deficient mice, egress from lymph nodes and Peyer's patches was markedly reduced, while nodal LYVE-1+ cortical sinuses lacked lymphocytes and appeared collapsed. Treatment with PTX to inhibit lymphocyte-Gi restored lymphocyte egress in these mice. Furthermore, we found in the absence of lymphatic Sphks, lymphatic vasculature architecture was altered. Together our findings support a model whereby lymphatic endothelial cells produce lymph S1P, which acts directly on lymphocyte S1P1 to overcome retention signals to promote lymphocyte egress from lymph nodes and Peyer's patches
G‐protein coupled receptors and ligands that organize humoral immune responses
No full textB-cell responses are dynamic processes that depend on multiple types of interactions. Rare antigen-specific B cells must encounter antigen and specialized systems are needed-unique to each lymphoid tissue type-to ensure this happens efficiently. Lymphoid tissue barrier cells act to ensure that pathogens, while being permitted entry for B-cell recognition, are blocked from replication or dissemination. T follicular helper (Tfh) cells often need to be primed by dendritic cells before supporting B-cell responses. For most responses, antigen-specific helper T cells and B cells need to interact, first to initiate clonal expansion and the plasmablast response, and later to support the germinal center (GC) response. Newly formed plasma cells need to travel to supportive niches. GC B cells must become confined to the follicle center, organize into dark and light zones, and interact with Tfh cells. Memory B cells need to be positioned for rapid responses following reinfection. Each of these events requires the actions of multiple G-protein coupled receptors (GPCRs) and their ligands, including chemokines and lipid mediators. This review will focus on the guidance cue code underlying B-cell immunity, with an emphasis on findings from our laboratory and on newer advances in related areas. We will discuss our recent identification of geranylgeranyl-glutathione as a ligand for P2RY8. Our goal is to provide the reader with a focused knowledge about the GPCRs guiding B-cell responses and how they might be therapeutic targets, while also providing examples of how multiple types of GPCRs can cooperate or act iteratively to control cell behavior
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The HVEM-BTLA axis restrains T cell help to germinal center B cells and functions as a cell-extrinsic suppressor in lymphomagenesis
No full textTNF receptor family member HVEM is one of the most frequently mutated surface proteins in germinal center (GC) derived B cell lymphomas, yet the role of HVEM in normal GCs is unknown. We found that HVEM-deficiency intrinsically increased B cell competitiveness during pre-GC and GC responses. The Ig superfamily molecule BTLA was identified as the ligand regulating these responses, and B cell-intrinsic signaling via HVEM and BTLA was not required. Instead, BTLA signaling into the T cell through SHP1 reduced TCR signaling and the amount of preformed CD40L mobilized to the immunological synapse and thus diminished the help delivered to B cells. Moreover, T cell-deficiency in BTLA cooperated with B cell Bcl-2-overexpression in leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells in a manner that influences GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis
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CXCR4 Promotes B Cell Egress from Peyer's Patches
No full textEffective surveillance of the lymph-borne milieu of foreign antigens requires the recirculation of lymphocytes. Their patrol takes them from the blood, into secondary lymphoid organs, and into lymph, from which they ultimately return to the blood. Much has been discovered about how this process unfolds at the microanatomic and molecular levels. However, understanding of how the mechanisms involved differ for mucosal immune tissues continues to develop.Peyer's patches (PPs) play a central role in supporting B cell responses against intestinal antigens, yet the factors controlling B cell passage through these mucosal lymphoid tissues are incompletely understood. Here we report that, in mixed chimeras, CXCR4-deficient B cells accumulate in PPs compared to their representation in other lymphoid tissues. CXCR4-deficient B cells egress from PPs more slowly than wild-type cells while CXCR5-deficient cells egress more rapidly. The CXCR4 ligand, CXCL12, is expressed by cells adjacent to lymphatic endothelial cells in a zone that abuts but minimally overlaps with the CXCL13+ follicle. CXCR4-deficient B cells show reduced localization to these CXCL12+ peri-lymphatic zones whereas CXCR5-deficient B cells preferentially localize in these regions. By photoconverting KikGR-expressing cells within surgically exposed PPs, we provide evidence that naïve B cells transit PPs with an approximate residency half-life of 10 h. When CXCR4 is lacking, KikGR+ B cells show a delay in PP egress. In summary, we identify a CXCL12hi peri-lymphatic zone in PPs that plays a role in overcoming CXCL13-mediated retention to promote B cell egress from these gut-associated lymphoid tissues
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Germinal Center Dark and Light Zone Organization and Cellular Dynamics
No full textThe germinal center (GC) is an important site for the generation and selection of B cells bearing high-affinity antibodies during an immune response. The GC is organized into two main compartments termed dark and light zones. However, despite extensive anatomical definition of these zones, the mechanisms by which GC compartmentalization and selection occur have remained poorly defined.First, we considered the possible role of chemokines as GC organizers. We show here that GC organization into dark and light zones was absent in mice deficient in the chemokine receptor CXCR4. GC B cells migrated toward the CXCR4 ligand SDF-1, which was more abundant in the dark zone than in the light zone. B cells in the dark zone expressed more CXCR4 than B cells in the light zone, and CXCR4-deficient B cells were excluded from the dark zone in the context of a wild-type GC. These findings suggest that CXCR4 promotes dark zone localization in response to SDF-1. In contrast, CXCR5 helped direct cells to the light zone, which is rich in the CXCR5 ligand CXCL13. Deficiency in CXCL13 was associated with aberrant positioning of the light zone.
To gain insight into the GC cell migration and interaction dynamics during selection, we imaged GCs in intact mouse lymph nodes by two-photon microscopy. We observed that GC B cells were highly motile and exhibited a dendritic morphology with long cell processes. GC B cell motility was partially dependent on the chemokine CXCL13. GC B cells transited between dark and light zones and divided in both zones, yet the cells resided in the light zone for only a few hours. GC B cells formed few stable contacts with GC T cells despite frequent encounters, and GC T cells were seen to carry dead GC B cell blebs. On the basis of these observations, we conclude that GC organization into dark and light zones is a chemokine-driven process. We also suggest a new model for selection in which competition for T cell help plays a more dominant role than previously appreciated
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