Publications by authors named "Susan R Schwab"

29 Publications

  • Page 1 of 1

Nilabh Shastri 1952-2021.

Nat Immunol 2021 May;22(5):533-534

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41590-021-00912-6DOI Listing
May 2021

Monocyte-derived S1P in the lymph node regulates immune responses.

Nature 2021 Apr 3;592(7853):290-295. Epub 2021 Mar 3.

Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, NY, USA.

The lipid chemoattractant sphingosine 1-phosphate (S1P) guides cells out of tissues, where the concentration of S1P is relatively low, into circulatory fluids, where the concentration of S1P is high. For example, S1P directs the exit of T cells from lymph nodes, where T cells are initially activated, into lymph, from which T cells reach the blood and ultimately inflamed tissues. T cells follow S1P gradients primarily using S1P receptor 1 (ref. ). Recent studies have described how S1P gradients are established at steady state, but little is known about the distribution of S1P in disease or about how changing levels of S1P may affect immune responses. Here we show that the concentration of S1P increases in lymph nodes during an immune response. We found that haematopoietic cells, including inflammatory monocytes, were an important source of this S1P, which was an unexpected finding as endothelial cells provide S1P to lymph. Inflammatory monocytes required the early activation marker CD69 to supply this S1P, in part because the expression of CD69 was associated with reduced levels of S1pr5 (which encodes S1P receptor 5). CD69 acted as a 'stand-your-ground' signal, keeping immune cells at a site of inflammation by regulating both the receptors and the gradients of S1P. Finally, increased levels of S1P prolonged the residence time of T cells in the lymph nodes and exacerbated the severity of experimental autoimmune encephalomyelitis in mice. This finding suggests that residence time in the lymph nodes might regulate the differentiation of T cells, and points to new uses of drugs that target S1P signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03227-6DOI Listing
April 2021

Endothelial S1P Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Circ Res 2021 Feb 2;128(3):363-382. Epub 2020 Dec 2.

Vascular Biology Program, Boston Children's Hospital, MA (T.H.).

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P modulation in stroke.

Objective: To address roles and mechanisms of engagement of endothelial cell S1P in the naive and ischemic brain and its potential as a target for cerebrovascular therapy.

Methods And Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P in the mouse brain. With an S1P signaling reporter, we reveal that abluminal polarization shields S1P from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion.

Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P agonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.120.316711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874503PMC
February 2021

Finding a Way Out: S1P Signaling and Immune Cell Migration.

Annu Rev Immunol 2020 04;38:759-784

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA; email:

The signaling lipid sphingosine 1-phosphate (S1P) plays critical roles in an immune response. Drugs targeting S1P signaling have been remarkably successful in treatment of multiple sclerosis, and they have shown promise in clinical trials for colitis and psoriasis. One mechanism of these drugs is to block lymphocyte exit from lymph nodes, where lymphocytes are initially activated, into circulation, from which lymphocytes can reach sites of inflammation. Indeed, S1P can be considered a circulation marker, signaling to immune cells to help them find blood and lymphatic vessels, and to endothelial cells to stabilize the vasculature. That said, S1P plays pleiotropic roles in the immune response, and it will be important to build an integrated view of how S1P shapes inflammation. S1P can function so effectively because its distribution is exquisitely tightly controlled. Here we review how S1P gradients regulate immune cell exit from tissues, with particular attention to key outstanding questions in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-immunol-081519-083952DOI Listing
April 2020

The Bone Marrow Protects and Optimizes Immunological Memory during Dietary Restriction.

Cell 2019 08;178(5):1088-1101.e15

Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Mammals evolved in the face of fluctuating food availability. How the immune system adapts to transient nutritional stress remains poorly understood. Here, we show that memory T cells collapsed in secondary lymphoid organs in the context of dietary restriction (DR) but dramatically accumulated within the bone marrow (BM), where they adopted a state associated with energy conservation. This response was coordinated by glucocorticoids and associated with a profound remodeling of the BM compartment, which included an increase in T cell homing factors, erythropoiesis, and adipogenesis. Adipocytes, as well as CXCR4-CXCL12 and S1P-S1PR interactions, contributed to enhanced T cell accumulation in BM during DR. Memory T cell homing to BM during DR was associated with enhanced protection against infections and tumors. Together, this work uncovers a fundamental host strategy to sustain and optimize immunological memory during nutritional challenges that involved a temporal and spatial reorganization of the memory pool within "safe haven" compartments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2019.07.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818271PMC
August 2019

Secrets and lyase: Control of sphingosine 1-phosphate distribution.

Immunol Rev 2019 05;289(1):173-185

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York City, New York.

The signaling lipid sphingosine 1-phosphate (S1P) plays key roles in many physiological processes. In the immune system, S1P's best-described function is to draw cells out of tissues into circulation. Here, we will review models of S1P distribution in the thymus, lymph nodes, spleen, and nonlymphoid tissues. These models have been challenging to construct, because of the lack of tools to map lipid gradients. Nonetheless, evidence to date suggests that S1P distribution is exquisitely tightly controlled, and that concentrations of signaling-available S1P cannot be predicted by standard rules of thumb. The fine regulation of S1P gradients may explain how S1P can simultaneously direct multiple cell movements both between tissues and circulation and within tissues. It may also make it feasible to develop drugs that enable spatially specific modulation of S1P signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imr.12760DOI Listing
May 2019

CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration.

Sci Immunol 2019 03;4(33)

Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) regulate migration of lymphocytes out of thymus to blood and lymph nodes (LNs) to efferent lymph, whereas their role in other tissue sites is not known. Here, we investigated the question of how these molecules regulate leukocyte migration from tissues through afferent lymphatics to draining LNs (dLNs). S1P, but not other chemokines, selectively enhanced human and murine CD4 T cell migration across lymphatic endothelial cells (LECs). T cell S1PR1 and S1PR4, and LEC S1PR2, were required for migration across LECs and into lymphatic vessels and dLNs. S1PR1 and S1PR4 differentially regulated T cell motility and vascular cell adhesion molecule-1 (VCAM-1) binding. S1PR2 regulated LEC layer structure, permeability, and expression of the junction molecules VE-cadherin, occludin, and zonulin-1 through the ERK pathway. S1PR2 facilitated T cell transcellular migration through VCAM-1 expression and recruitment of T cells to LEC migration sites. These results demonstrated distinct roles for S1PRs in comodulating T cell and LEC functions in migration and suggest previously unknown levels of regulation of leukocytes and endothelial cells during homeostasis and immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.aav1263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744614PMC
March 2019

PreB cells are moving on.

J Exp Med 2018 10 18;215(10):2483-2484. Epub 2018 Sep 18.

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY

In this issue of , Fistonich et al. (https://doi.org/10.1084/jem.20180778) address how the bone marrow microenvironment supports diverse lineages through multiple developmental stages. Differential motility between pro- and preB cells results in differential IL-7 exposure, and, intriguingly, stromal cells respond to abnormal B cells by reducing .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20181503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170175PMC
October 2018

Have Cytokines, Will Travel.

Immunity 2018 02;48(2):200-201

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA. Electronic address:

In many contexts, innate lymphoid cells (ILCs) are primarily tissue resident. By contrast, in a recent issue of Science, Huang et al. (2018) show that inflammatory type 2 ILCs migrate from the intestine to the lungs and that this movement is guided by sphingosine-1-phosphate receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2018.02.007DOI Listing
February 2018

Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells.

Nature 2017 06 24;546(7656):158-161. Epub 2017 May 24.

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.

Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P receptor (S1PR) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1PR on T cells, and that the requirement for S1PR is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature22352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683179PMC
June 2017

HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P) promotes regeneration and suppresses fibrosis in the liver.

JCI Insight 2016 Dec 22;1(21):e87058. Epub 2016 Dec 22.

Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.

Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this "maladaptive repair" phenotype was recapitulated in mice that lack S1P in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.87058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161208PMC
December 2016

Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response.

Nat Immunol 2017 01 14;18(1):15-25. Epub 2016 Nov 14.

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.

The lymph node periphery is an important site for many immunological functions, from pathogen containment to the differentiation of helper T cells, yet the cues that position cells in this region are largely undefined. Here, through the use of a reporter for the signaling lipid S1P (sphingosine 1-phosphate), we found that cells sensed higher concentrations of S1P in the medullary cords than in the T cell zone and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this gradient. Natural killer (NK) cells are located at the periphery of the lymph node, predominantly in the medulla, and we found that expression of SPNS2, expression of the S1P receptor S1PR5 on NK cells, and expression of the chemokine receptor CXCR4 were all required for NK cell localization during homeostasis and rapid production of interferon-γ by NK cells after challenge. Our findings elucidate the spatial cues for NK cell organization and reveal a previously unknown role for S1P in positioning cells within the medulla.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni.3619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675020PMC
January 2017

Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus.

Nat Commun 2016 Feb 29;7:10562. Epub 2016 Feb 29.

Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.

Regulatory T-cell (Treg) selection in the thymus is essential to prevent autoimmune diseases. Although important rules for Treg selection have been established, there is controversy regarding the degree of self-reactivity displayed by T-cell receptors expressed by Treg cells. In this study we have developed a model of autoimmune skin inflammation, to determine key parameters in the generation of skin-reactive Treg cells in the thymus (tTreg). tTreg development is predominantly AIRE dependent, with an AIRE-independent component. Without the knowledge of antigen recognized by skin-reactive Treg cells, we are able to enhance skin-specific tTreg cell generation using three approaches. First, we increase medullary thymic epithelial cells by using mice lacking osteoprotegerin or by adding TRANCE (RANKL, Tnfsf11). Second, we inject intrathymically peripheral dendritic cells from skin-draining sites. Finally, we inject skin tissue lysates intrathymically. These findings have implications for enhancing the generation of organ-specific Treg cells in autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms10562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773449PMC
February 2016

Exit Strategies: S1P Signaling and T Cell Migration.

Trends Immunol 2015 Dec;36(12):778-787

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Whereas the role of sphingosine 1-phosphate receptor 1 (S1PR1) in T cell egress and the regulation of S1P gradients between lymphoid organs and circulatory fluids in homeostasis are increasingly well understood, much remains to be learned about S1P signaling and distribution during an immune response. Recent data suggest that the role of S1PR1 in directing cells from tissues into circulatory fluids is reprised again and again, particularly in guiding activated T cells from non-lymphoid tissues into lymphatics. Conversely, S1P receptor 2 (S1PR2), which antagonizes migration towards chemokines, confines cells within tissues. Here we review the current understanding of the roles of S1P signaling in activated T cell migration. In this context, we outline open questions, particularly regarding the shape of S1P gradients in different tissues in homeostasis and inflammation, and discuss recent strategies to measure S1P.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.it.2015.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832571PMC
December 2015

A map of the distribution of sphingosine 1-phosphate in the spleen.

Nat Immunol 2015 Dec 26;16(12):1245-52. Epub 2015 Oct 26.

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.

Despite the importance of signaling lipids, many questions remain about their function because few tools are available for charting lipid gradients in vivo. Here we generated a sphingosine 1-phosphate (S1P) reporter mouse and used this mouse to define the distribution of S1P in the spleen. Unexpectedly, the presence of blood did not serve as a predictor of the concentration of signaling-available S1P. Large areas of the red pulp had low concentrations of S1P, while S1P was sensed by cells inside the white pulp near the marginal sinus. The lipid phosphate phosphatase LPP3 maintained low S1P concentrations in the spleen and enabled efficient shuttling of marginal zone B cells. The exquisitely tight regulation of S1P availability might explain how a single lipid can simultaneously orchestrate the movements of many cells of the immune system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni.3296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690472PMC
December 2015

CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance.

Cancer Cell 2015 Jun;27(6):755-68

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address:

The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2015.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461838PMC
June 2015

Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX(3)CR1(hi) cells.

Nature 2013 Feb 13;494(7435):116-20. Epub 2013 Jan 13.

Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX(3)CR1(hi) mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory. These findings define a central role for commensals in regulating the migration to the MLNs of CX(3)CR1(hi) mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature11809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711636PMC
February 2013

The transporter Spns2 is required for secretion of lymph but not plasma sphingosine-1-phosphate.

Cell Rep 2012 Nov 25;2(5):1104-10. Epub 2012 Oct 25.

Program in Molecular Pathogenesis and Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.

Plasma sphingosine-1-phosphate (S1P) regulates vascular permeability, and plasma and lymph S1P guide lymphocyte egress from lymphoid organs. S1P is made intracellularly, and little is known about how S1P is delivered into circulatory fluids. Here, we find that mice without the major facilitator superfamily transporter Spns2 have a profound reduction in lymph S1P, but only a minor decrease in plasma S1P. Spns2-deficient mice have a redistribution of lymphocytes from the spleen to lymph nodes and a loss of circulating lymphocytes, consistent with normal egress from the spleen directed by plasma S1P and blocked egress from lymph nodes directed by lymph S1P. Spns2 is needed in endothelial cells to supply lymph S1P and support lymphocyte circulation. As a differential requirement for lymph and blood S1P, Spns2 may be an attractive target for immune suppressive drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2012.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616498PMC
November 2012

Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.

Annu Rev Immunol 2012 5;30:69-94. Epub 2011 Dec 5.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, California 94143-0414, USA.

Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-immunol-020711-075011DOI Listing
July 2012

Lipid phosphate phosphatase 3 enables efficient thymic egress.

J Exp Med 2011 Jun 16;208(6):1267-78. Epub 2011 May 16.

Program in Molecular Pathogenesis and Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20102551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173249PMC
June 2011

Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning.

J Exp Med 2010 Jan 21;207(1):17-27. Epub 2009 Dec 21.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.

Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Galphai-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell-cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20091619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812554PMC
January 2010

Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells.

Nat Immunol 2009 Jan 7;10(1):58-65. Epub 2008 Dec 7.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California 94143, USA.

The cellular dynamics of the egress of lymphocytes from lymph nodes are poorly defined. Here we visualized the branched organization of lymph node cortical sinuses and found that after entry, some T cells were retained, whereas others returned to the parenchyma. T cells deficient in sphingosine 1-phosphate receptor type 1 probed the sinus surface but failed to enter the sinuses. In some sinuses, T cells became rounded and moved unidirectionally. T cells traveled from cortical sinuses into macrophage-rich sinus areas. Many T cells flowed from medullary sinuses into the subcapsular space. We propose a multistep model of lymph node egress in which cortical sinus probing is followed by entry dependent on sphingosine 1-phosphate receptor type 1, capture of cells in a sinus region with flow, and transport to medullary sinuses and the efferent lymph.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni.1682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710451PMC
January 2009

Finding a way out: lymphocyte egress from lymphoid organs.

Nat Immunol 2007 Dec;8(12):1295-301

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.

The egress of lymphocytes from the thymus and secondary lymphoid organs into circulatory fluids is essential for normal immune function. The discovery that a small-molecule inhibitor of lymphocyte exit, FTY720, is a ligand for sphingosine 1-phosphate (S1P) receptors led to studies demonstrating that S1P receptor type 1 (S1P1) is needed in T cells and B cells for their egress from lymphoid organs. S1P exists in higher concentrations in blood and lymph than in lymphoid organs, and this differential is also required for lymphocyte exit. Transcriptional and post-translational mechanisms regulate S1P1 and thus the egress of lymphocytes. In this review we discuss the body of evidence supporting a model in which lymphocyte egress is promoted by encounter with S1P at exit sites. We relate this model to work examining the effects of S1P receptor agonists on endothelium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni1545DOI Listing
December 2007

Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate.

Science 2007 Apr 15;316(5822):295-8. Epub 2007 Mar 15.

Cardiovascular Research Institute, University of California, San Francisco, 600 16th Street S472D, San Francisco, CA 94143-2240, USA.

Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1139221DOI Listing
April 2007

All the peptides that fit: the beginning, the middle, and the end of the MHC class I antigen-processing pathway.

Immunol Rev 2005 Oct;207:31-41

Department of Molecular and Cell Biology, Division of Immunology, University of California, Berkeley, CA 94720, USA.

The end result of the antigen-processing pathway is the display of peptide-bound major histocompatibility complex I (pMHC I) molecules. The pMHC I molecules are expressed on the cell surface where they can be surveyed by CD8(+) T cells for abnormal proteins. MHC I molecules present a large repertoire of peptides that fit perfectly in their binding grooves and represent the otherwise hidden intracellular contents. Many peptides originate as defective ribosomal products in the cytoplasm. In a stepwise manner, the antigen-processing pathway generates and protects the proteolytic intermediates until they yield the final peptides that can fit the MHC I in the endoplasmic reticulum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.0105-2896.2005.00321.xDOI Listing
October 2005

Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.

Science 2005 Sep;309(5741):1735-9

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0414, USA.

Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 and is thought to occur in response to circulatory S1P. However, the existence of an S1P gradient between lymphoid organs and blood or lymph has not been established. To further define egress requirements, we addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. We found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after THI treatment and that this treatment inhibits the S1P-degrading enzyme S1P lyase. We conclude that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1113640DOI Listing
September 2005

Unanticipated antigens: translation initiation at CUG with leucine.

PLoS Biol 2004 Nov 26;2(11):e366. Epub 2004 Oct 26.

Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.

Major histocompatibility class I molecules display tens of thousands of peptides on the cell surface for immune surveillance by T cells. The peptide repertoire represents virtually all cellular translation products, and can thus reveal a foreign presence inside the cell. These peptides are derived from not only conventional but also cryptic translational reading frames, including some without conventional AUG codons. To define the mechanism that generates these cryptic peptides, we used T cells as probes to analyze the peptides generated in transfected cells. We found that when CUG acts as an alternate initiation codon, it can be decoded as leucine rather than the expected methionine residue. The leucine start does not depend on an internal ribosome entry site-like mRNA structure, and its efficiency is enhanced by the Kozak nucleotide context. Furthermore, ribosomes scan 5' to 3' specifically for the CUG initiation codon in a eukaryotic translation initiation factor 2-independent manner. Because eukaryotic translation initiation factor 2 is frequently targeted to inhibit protein synthesis, this novel translation mechanism allows stressed cells to display antigenic peptides. This initiation mechanism could also be used at non-AUG initiation codons often found in viral transcripts as well as in a growing list of cellular genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.0020366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524250PMC
November 2004

Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF.

Immunity 2004 Apr;20(4):441-53

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 USA.

Peripheral autoantigen binding B cells are poorly competitive with naive B cells for survival and undergo rapid cell death. However, in monoclonal Ig-transgenic mice lacking competitor B cells, autoantigen binding B cells can survive for extended periods. The basis for competitive elimination of autoantigen binding B cells has been unknown. Here we demonstrate that autoantigen binding B cells have increased dependence on BAFF for survival. In monoclonal Ig-transgenic mice, each autoantigen binding B cell receives elevated amounts of BAFF, exhibiting increased levels of NFkappaB p52 and of the prosurvival kinase Pim2. When placed in a diverse B cell compartment, BAFF receptor engagement and signaling are reduced and the autoantigen binding cells are unable to protect themselves from Bim and possibly other death-promoting factors induced by chronic BCR signaling. These findings indicate that under conditions where BAFF levels are elevated, autoantigen-engaged cells will be rescued from rapid competitive elimination, predisposing to the development of autoimmune disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s1074-7613(04)00079-2DOI Listing
April 2004

Constitutive display of cryptic translation products by MHC class I molecules.

Science 2003 Sep;301(5638):1367-71

Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.

Major histocompatibility complex (MHC) class I molecules display tens of thousands of peptides on the cell surface, derived from virtually all endogenous proteins, for inspection by cytotoxic T cells (CTLs). We show that, in normal mouse cells, MHC I molecules present a peptide encoded in the 3' "untranslated" region. Despite its rarity, the peptide elicits CTL responses and induces self-tolerance, establishing that immune surveillance extends well beyond conventional polypeptides. Furthermore, translation of this cryptic peptide occurs by a previously unknown mechanism that decodes the CUG initiation codon as leucine rather than the canonical methionine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1085650DOI Listing
September 2003