Showing papers by "Jason G. Cyster published in 2014"

25-Hydroxycholesterol suppresses interleukin-1–driven inflammation downstream of type I interferon

Abstract: Type I interferon (IFN) protects against viruses, yet it also has a poorly understood suppressive influence on inflammation. Here, we report that activated mouse macrophages lacking the IFN-stimulated gene cholesterol 25-hydroxylase ( Ch25h ) and that are unable to produce the oxysterol 25-hydroxycholesterol (25-HC) overproduce inflammatory interleukin-1 (IL-1) family cytokines. 25-HC acts by antagonizing sterol response element–binding protein (SREBP) processing to reduce Il1b transcription and to broadly repress IL-1–activating inflammasomes. In accord with these dual actions of 25-HC, Ch25h-deficient mice exhibit increased sensitivity to septic shock, exacerbated experimental autoimmune encephalomyelitis, and a stronger ability to repress bacterial growth. These findings identify an oxysterol, 25-HC, as a critical mediator in the negative-feedback pathway of IFN signaling on IL-1 family cytokine production and inflammasome activity.

25-Hydroxycholesterols in innate and adaptive immunity

Abstract: Cholesterol and components of the cholesterol biosynthetic pathway have fundamental roles in all mammalian cells. Hydroxylated forms of cholesterol are now emerging as important regulators of immune function. This involves effects on the cholesterol biosynthetic pathway and cell membrane properties, which can have antiviral and anti-inflammatory influences. In addition, a dihydroxylated form of cholesterol functions as an immune cell guidance cue by engaging the G protein-coupled receptor EBI2, and it is required for mounting adaptive immune responses. In this Review, we summarize the current understanding of the closely related oxysterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, and the growing evidence that they have wide-ranging influences on innate and adaptive immunity.

Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma

Abstract: Function-disrupting mutations in the S1PR2G13ARHGEF1 signalling pathway are common in one of the most frequent classes of non-Hodgkin's lymphoma, germinal centre B-celllike diffuse large B-cell lymphoma (GCB-DLBCL). This paper shows that inactivation of this signalling pathway in mice allows Akt activation and promotes dissemination of germinal centre B cells, consistent with a role of function-disrupting mutations in the systemic dissemination of large B-cell lymphoma.

Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers.

Abstract: Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. We report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared with T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses.

CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow.

Abstract: Leukocyte residence in lymphoid organs is controlled by a balance between retention and egress-promoting chemoattractants sensed by pertussis toxin (PTX)–sensitive Gαi protein–coupled receptors (GPCRs). Here, we use two-photon intravital microscopy to show that immature B cell retention within bone marrow (BM) was strictly dependent on amoeboid motility mediated by CXCR4 and CXCL12 and by α4β1 integrin–mediated adhesion to VCAM-1. However, B lineage cell egress from BM is independent of PTX-sensitive GPCR signaling. B lineage cells expressing PTX rapidly exited BM even though their motility within BM parenchyma was significantly reduced. Our experiments reveal that when immature B cells are near BM sinusoids their motility is reduced, their morphology is predominantly rounded, and cells reverse transmigrate across sinusoidal endothelium in a largely nonamoeboid manner. Immature B cell egress from BM was dependent on a twofold CXCR4 down-regulation that was antagonized by antigen-induced BCR signaling. This passive mode of cell egress from BM also contributes significantly to the export of other hematopoietic cells, including granulocytes, monocytes, and NK cells, and is reminiscent of erythrocyte egress.

GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment

Abstract: Intraepithelial lymphocytes (IELs) play an important role in maintaining the physiology of the small intestine. The majority of mouse IELs express CD8αα and are either γδ or αβ T cells. Although the development and homing of CD8αα IELs have been studied in some detail, the factors controlling their homeostasis and positioning are incompletely understood. Here we demonstrate that G protein–coupled receptor 18 (GPR18) is abundantly expressed in CD8αα IELs and that mice lacking this orphan receptor have reduced numbers of γδT IELs. Mixed bone marrow chimera experiments reveal a markedly reduced contribution of GPR18-deficient cells to the CD8αα IEL compartment and a reduction in the CD8αβ T cell subset. These defects could be rescued by transduction with a GPR18-expressing retrovirus. The GPR18-deficient γδT IELs that remained in mixed chimeras had elevated Thy1, and there were less granzyme B+ and Vγ7+ cells, indicating a greater reduction in effector-type cells. Flow cytometric analysis indicated GPR18 deficiency more strongly affected the CD8αα cells in the intraepithelial compared with the adjacent lamina propria compartment. These findings establish a requirement for GPR18 in CD8αα and CD8αβ IELs, and we suggest the receptor has a role in augmenting the accumulation of CD8 T cells in the intraepithelial versus lamina propria compartment.

Integrin-Mediated Interactions between B Cells and Follicular Dendritic Cells Influence Germinal Center B Cell Fitness

Abstract: Integrin-ligand interactions between germinal center (GC) B cells and Ag-presenting follicular dendritic cells (FDCs) have been suggested to play central roles during GC responses, but their in vivo requirement has not been directly tested. In this study, we show that, whereas integrins αLβ2 and α4β1 are highly expressed and functional on mouse GC B cells, removal of single integrins or their ligands had little effect on B cell participation in the GC response. Combined β2 integrin deficiency and α4 integrin blockade also did not affect the GC response against a particulate Ag. However, the combined integrin deficiency did cause B cells to be outcompeted in splenic GC responses against a soluble protein Ag and in mesenteric lymph node GC responses against gut-derived Ags. Similar findings were made for β2-deficient B cells in mice lacking VCAM1 on FDCs. The reduced fitness of the GC B cells did not appear to be due to decreased Ag acquisition, proliferation rates, or pAKT levels. In summary, our findings provide evidence that αLβ2 and α4β1 play overlapping and context-dependent roles in supporting interactions with FDCs that can augment the fitness of responding GC B cells. We also find that mouse GC B cells upregulate αvβ3 and adhere to vitronectin and milk-fat globule epidermal growth factor VIII protein. Integrin β3-deficient B cells contributed in a slightly exaggerated manner to GC responses, suggesting this integrin has a regulatory function in GC B cells.

Blood, sphingosine-1-phosphate and lymphocyte migration dynamics in the spleen.

Abstract: The spleen, the largest secondary lymphoid organ, has long been known to play important roles in immunity against blood-borne invaders. Yet how cells migrate within the spleen to ensure fast and effective responses is only now coming to light. Chemokines and oxysterols guide lymphocytes from sites of release at terminal arterioles into the lymphocyte-rich white pulp. Sphingosine-1-phosphate (S1P) and S1P-receptor-1 (S1PR1) promote lymphocyte egress from white to red pulp and back to circulation. Intravital two-photon microscopy has shown that marginal zone (MZ) B cells that are enriched between white and red pulps undergo continual oscillatory migration between the MZ and follicles, ferrying antigens. Cycles of G-protein-coupled receptor kinase-2 (GRK2) mediated S1PR1 desensitization and resensitization underlie this remarkable behavior. The findings discussed in this review have implications for understanding how splenic antibody and T-cell responses are mounted, how the immunosuppressant drug FTY720 (fingolimod) affects the spleen, and how cell shuttling behaviors contribute to immunity.

Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment

Abstract: To defend our bodies against a variety of foreign microbes, our immune system makes cells called T cells that can identify these invaders and help to destroy them. There are several types of T cells that play different roles in the immune response: some activate other immune cells, while others destroy cells that have been infected by viruses or other pathogens. T cells develop in a specialized organ called the thymus, where they go through a rigorous selection process before being released as mature T cells into the rest of the body. This selection process includes eliminating individual T cells that are found to be sub-standard, perhaps because they might mistake our own cells for enemy cells. However, many of the details of the later stages of T cell development are not fully understood. Han et al. have now found that a protein called Zfp335 that is involved in the production of mature T cells. Mice carrying a mutation in the gene that makes this protein have fewer mature T cells than normal mice. Han et al. also reveal that Zfp335 is a transcription factor that can control whether or not other genes are expressed as proteins, and further show that one of these proteins, Ankle2, has an important role in the production of mature T cells. A next step in the work is to define exactly how Zfp335 controls the expression of these genes. It will also be important to determine whether mutations in Zfp335 contribute to human T-cell immunodeficiency.

Blown Away: The Unexpected Role of Lymphotoxin in Lymphoid Organ Development

Abstract: Lymph nodes (LNs), Peyer’s patches (PPs), and the spleen are command centers for the adaptive immune system, bringing together Ags and immune cells for the initiation of antipathogen offensives. The anatomy of these organs has been studied for over 100 years, and their organization into thymus-