Sebastian Joyce

Publications of Sebastian Joyce

• IL-15 regulates homeostasis and terminal maturation of NKT cells.

  Authors: Laura E Gordy, Jelena S Bezbradica, Andrew I Flyak, Charles T Spencer, Alexis Dunkle, Jingchun Sun, Aleksandar K Stanic, Mark R Boothby, You-Wen He, Zhongming Zhao, Luc Van Kaer, Sebastian Joyce

  Journal of immunology (Baltimore, Md. : 1950). 11/2011; 187(12):6335-45.

  Semi-invariant NKT cells are thymus-derived innate-like lymphocytes that modulate microbial and tumor immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells areSemi-invariant NKT cells are thymus-derived innate-like lymphocytes that modulate microbial and tumor immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learned regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL-15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-x(L) expression. Additionally, IL-15 regulated thymic developmental stage 2 to stage 3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic NKT cells. The loss of IL-15 also resulted in poor expression of key effector molecules such as IFN-γ, granzyme A and C, as well as several NK cell receptors, which are also regulated by T-bet in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-x(L), and effector differentiation, which is consistent with a role of T-bet in regulating terminal maturation.

• NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors.

  Authors: Sebastian Joyce, Enrico Girardi, Dirk M Zajonc

  Journal of immunology (Baltimore, Md. : 1950). 08/2011; 187(3):1081-9.

  NKT cells that express the semi-invariant TCR are innate-like lymphocytes whose functions are regulated by self and foreign glycolipid ligands presented by the Ag-presenting, MHC class I-likeNKT cells that express the semi-invariant TCR are innate-like lymphocytes whose functions are regulated by self and foreign glycolipid ligands presented by the Ag-presenting, MHC class I-like molecule CD1d. Activation of NKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers, and self-antigens. The nature of CD1d-restricted ligands, the manner in which they are recognized, and the unique effector functions of NKT cells suggest an immunoregulatory role for this T cell subset. Their ability to respond fast and our ability to steer NKT cell cytokine response to altered lipid ligands make them an important target for vaccine design and immunotherapies against autoimmune diseases. This review summarizes our current understanding of CD1d-restricted ligand recognition by NKT cells and how these innate-like lymphocytes regulate inflammation.

• Proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with antigen processing control CD4+ Th cell responses by regulating indirect presentation of MHC class II-restricted cytoplasmic antigens.

  Authors: Srdjan M Dragovic, Timothy Hill, Gregory J Christianson, Sungjune Kim, Tim Elliott, Diane Scott, Derry C Roopenian, Luc Van Kaer, Sebastian Joyce

  Journal of immunology (Baltimore, Md. : 1950). 06/2011; 186(12):6683-92.

  Cytoplasmic Ags derived from viruses, cytosolic bacteria, tumors, and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professionalCytoplasmic Ags derived from viruses, cytosolic bacteria, tumors, and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professional APCs acquire them during uptake of dead class II-negative cells and present them via a process called indirect presentation. It is generally assumed that the cytosolic Ag-processing machinery, which supplies peptides for presentation by class I molecules, plays very little role in indirect presentation of class II-restricted cytoplasmic Ags. Remarkably, upon testing this assumption, we found that proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with Ag processing, but not tapasin, partially destroyed or removed cytoplasmic class II-restricted Ags, such that their inhibition or deficiency led to dramatically increased Th cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags, both of which are indirectly presented. This effect was neither due to enhanced endoplasmic reticulum-associated degradation nor competition for Ag between class I and class II molecules. From these findings, a novel model emerged in which the cytosolic Ag-processing machinery regulates the quantity of cytoplasmic peptides available for presentation by class II molecules and, hence, modulates Th cell responses.

• Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1.

  Authors: Kimberly C Boelte, Laura E Gordy, Sebastian Joyce, Mary Ann Thompson, Li Yang, P Charles Lin

  PloS one. 01/2011; 6(4):e18534.

  Tumor growth is intimately linked with stromal interactions. Myeloid derived suppressor cells (MDSCs) are dramatically elevated in cancer patients and tumor bearing mice. MDSCs modulate the tumorTumor growth is intimately linked with stromal interactions. Myeloid derived suppressor cells (MDSCs) are dramatically elevated in cancer patients and tumor bearing mice. MDSCs modulate the tumor microenvironment through attenuating host immune response and increasing vascularization. In searching for molecular mediators responsible for pro-tumor functions, we found that regulator of G protein signaling-2 (Rgs2) is highly increased in tumor-derived MDSCs compared to control MDSCs. We further demonstrate that hypoxia, a common feature associated with solid tumors, upregulates the gene expression. Genetic deletion of Rgs2 in mice resulted in a significant retardation of tumor growth, and the tumors exhibit decreased vascular density and increased cell death. Interestingly, deletion of Rgs2 in MDSCs completely abolished their tumor promoting function, suggesting that Rgs2 signaling in MDSCs is responsible for the tumor promoting function. Cytokine array profiling identified that Rgs2-/- tumor MDSCs produce less MCP-1, leading to decreased angiogenesis, which could be restored with addition of recombinant MCP-1. Our data reveal Rgs2 as a critical regulator of the pro-angiogenic function of MDSCs in the tumor microenvironment, through regulating MCP-1 production.

• The hunt for iNKT cell antigens: alpha-galactosidase-deficient mice to the rescue?

  Authors: Luc Van Kaer, Sebastian Joyce

  Immunity. 08/2010; 33(2):143-5.

  The endogenous lipids that control the functions of invariant natural killer T (iNKT) cells remain enigmatic. In this issue of Immunity, Darmoise et al. (2010) report that lysosomalThe endogenous lipids that control the functions of invariant natural killer T (iNKT) cells remain enigmatic. In this issue of Immunity, Darmoise et al. (2010) report that lysosomal alpha-galactosidase A destroys self-antigens recognized by iNKT cells.

• Follicular B cell trafficking within the spleen actively restricts humoral immune responses.

  Authors: Kristen L Hoek, Laura E Gordy, Patrick L Collins, Vrajesh V Parekh, Thomas M Aune, Sebastian Joyce, James W Thomas, Luc Van Kaer, Eric Sebzda

  Immunity. 08/2010; 33(2):254-65.

  Follicular (FO) and marginal zone (MZ) B cells are maintained in distinct locations within the spleen, but the genetic basis for this separation is still enigmatic. We now report that B cellFollicular (FO) and marginal zone (MZ) B cells are maintained in distinct locations within the spleen, but the genetic basis for this separation is still enigmatic. We now report that B cell sequestration requires lineage-specific regulation of migratory receptors by the transcription factor Klf2. Moreover, using gene-targeted mice we show that altered splenic B cell migration confers a significant in vivo gain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associated antigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals, naive FO B cells are actively removed from the MZ, thus restricting their capacity to respond to blood-borne pathogens.

• Minor histocompatibility antigens: presentation principles, recognition logic and the potential for a healing hand.

  Authors: Charles T Spencer, Pavlo Gilchuk, Srdjan M Dragovic, Sebastian Joyce

  Current opinion in organ transplantation. 08/2010; 15(4):512-25.

  There is ample evidence indicating a pathologic role for minor histocompatibility antigens in inciting graft-versus-host disease in major histocompatibility complex (MHC)-matched bone marrowThere is ample evidence indicating a pathologic role for minor histocompatibility antigens in inciting graft-versus-host disease in major histocompatibility complex (MHC)-matched bone marrow transplantation and rejection of solid organ allografts. Here we review the current knowledge of the genetic and biochemical bases for the cause of minor histoincompatibility and the structural basis for the recognition of the resulting alloantigens by the T-cell receptor. Recent evidence indicates that we as independently conceived individuals are genetically unique, thus, offering a mechanism for minor histoincompatibility between MHC-identical donor-recipient pairs. Furthermore, advances in delineating the mechanisms underlying antigen cross-presentation by MHC class I molecules and a critical role for autophagy in presenting cytoplasmic antigens by MHC class II molecules have been made. These new insights coupled with the X-ray crystallographic solution of several peptide/MHC-T-cell receptor structures have revealed mechanisms of histoincompatibility. On the basis of these new insights, ways to test for allograft compatibility and concoction of immunotherapies are discussed.

• Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways.

  Authors: Keunwook Lee, Prathyusha Gudapati, Srdjan Dragovic, Charles Spencer, Sebastian Joyce, Nigel Killeen, Mark A Magnuson, Mark Boothby

  Immunity. 06/2010; 32(6):743-53.

  Many functions of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) have been defined, but relatively little is known about the biology of an alternative mTOR complex, mTORC2. We showedMany functions of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) have been defined, but relatively little is known about the biology of an alternative mTOR complex, mTORC2. We showed that conditional deletion of rictor, an essential subunit of mTORC2, impaired differentiation into T helper 1 (Th1) and Th2 cells without diversion into FoxP3(+) status or substantial effect on Th17 cell differentiation. mTORC2 promoted phosphorylation of protein kinase B (PKB, or Akt) and PKC, Akt activity, and nuclear NF-kappaB transcription factors in response to T cell activation. Complementation with active Akt restored only T-bet transcription factor expression and Th1 cell differentiation, whereas activated PKC-theta reverted only GATA3 transcription factor and the Th2 cell defect of mTORC2 mutant cells. Collectively, the data uncover vital mTOR-PKC and mTOR-Akt connections in T cell differentiation and reveal distinct pathways by which mTORC2 regulates development of Th1 and Th2 cell subsets.

• Natural killer T cell-a cat o' nine lives!

  Authors: Sebastian Joyce, Laura E Gordy

  The EMBO journal. 05/2010; 29(9):1475-6.

• Neurons Preferentially Respond to Self-MHC Class I Allele Products Regardless of Peptide Presented.

  Authors: Nathalie Escande-Beillard, Lorraine Washburn, Dan Zekzer, Zhongqi-Phyllis Wu, Shoshy Eitan, Sonja Ivkovic, Yuxin Lu, Hoa Dang, Blake Middleton, Tina V Bilousova, Yoshitaka Yoshimura, Christopher J Evans, Sebastian Joyce, Jide Tian, Daniel L Kaufman

  Journal of immunology (Baltimore, Md. : 1950). 12/2009;

  Studies of mice lacking MHC class I (MHC I)-associated proteins have demonstrated a role for MHC I in neurodevelopment. A central question arising from these observations is whether neuronalStudies of mice lacking MHC class I (MHC I)-associated proteins have demonstrated a role for MHC I in neurodevelopment. A central question arising from these observations is whether neuronal recognition of MHC I has specificity for the MHC I allele product and the peptide presented. Using a well-established embryonic retina explant system, we observed that picomolar levels of a recombinant self-MHC I molecule inhibited neurite outgrowth. We then assessed the neurobiological activity of a panel of recombinant soluble MHC Is, consisting of different MHC I heavy chains with a defined self- or nonself-peptide presented, on cultured embryonic retinas from mice with different MHC I haplotypes. We observed that self-MHC I allele products had greater inhibitory neuroactivity than nonself-MHC I molecules, regardless of the nature of the peptide presented, a pattern akin to MHC I recognition by some innate immune system receptors. However, self-MHC I molecules had no effect on retinas from MHC I-deficient mice. These observations suggest that neuronal recognition of MHC I may be coordinated with the inherited MHC I alleles, as occurs in the innate immune system. Consistent with this notion, we show that MHC I and MHC I receptors are coexpressed by precursor cells at the earliest stages of retina development, which could enable such coordination.

• Adaptability of the semi-invariant natural killer T-cell receptor towards structurally diverse CD1d-restricted ligands.

  Authors: William C Florence, Chengfeng Xia, Laura E Gordy, Wenlan Chen, Yalong Zhang, James Scott-Browne, Yuki Kinjo, Karl O A Yu, Santosh Keshipeddy, Daniel G Pellicci [......] Dale I Godfrey, Jamie Rossjohn, Stewart K Richardson, Steven A Porcelli, Amy R Howell, Kyoko Hayakawa, Laurent Gapin, Dirk M Zajonc, Peng George Wang, Sebastian Joyce

  The EMBO journal. 12/2009; 28(23):3781.

• IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD.

  Authors: Alejandro V Villarino, David Artis, Jelena S Bezbradica, Omer Miller, Christiaan J M Saris, Sebastian Joyce, Christopher A Hunter

  International immunology. 07/2008; 20(6):739-52.

  Members of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis inMembers of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis in mice. We report that, compared with IL-10-deficient animals, which succumb to chronic intestinal disease at 3-6 months of age, mice lacking both IL-10 and the IL-27R (IL-27R/WSX-1) exhibit delayed pathology and prolonged survival (>1 year). Moreover, unlike highly susceptible IL-10-deficient counterparts, they were able to clear infection with Trichuris muris, a colon-dwelling nematode. In both models of intestinal inflammation, improved clinical outcome was associated with reduced inflammation and profound attenuation of T(h)1 responses and, consistent with these in vivo findings, we confirmed that during in vitro differentiation, IL-27 directly promotes CD4(+) T cell IFN-gamma production through effects on Tbet, a key T(h)1 transcription factor. We also found that its ability to suppress T(h)2 responses, which was clearly evident in helminth-infected IL-10-/-IL-27R-/- mice, was largely Tbet independent. Taken together, these studies demonstrate that, in the absence of IL-10, IL-27 can promote T(h)1-type and suppress T(h)2-type intestinal inflammation but, ultimately, is not required for the development of inflammatory bowel disease.

• Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo.

  Authors: Chang-Yuan Ni, Zhao-Hui Wu, William C Florence, Vrajesh V Parekh, Maria Pia Arrate, Steven Pierce, Brock Schweitzer, Luc Van Kaer, Sebastian Joyce, Shigeki Miyamoto, Dean W Ballard, Eugene M Oltz

  Journal of immunology (Baltimore, Md. : 1950). 07/2008; 180(11):7107-11.

  Transcription factor NF-kappaB controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-kappaB signaling is regulated byTranscription factor NF-kappaB controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-kappaB signaling is regulated by posttranslational modifications to IkappaB kinase, which earmarks inhibitors of NF-kappaB for degradation. Prior studies suggest that K63-linked ubiquitination of NEMO (NF-kappaB essential modulator), an IkappaB kinase regulatory subunit, is critical for NF-kappaB and MAPK signaling following engagement of Ag receptors. We now demonstrate that NF-kappaB and MAPK pathways are largely unaffected in primary cells from mice harboring a ubiquitination-defective form of NEMO, NEMO-KR. TLR- but not Ag receptor-induced cellular responses are impaired in NEMO-KR mice, which are more resistant to LPS-induced endotoxic shock than wild-type animals. Thus, one function of NEMO ubiquitination is to fine tune innate immune responses under TLR control.

• Lung NKT cell commotion takes your breath away.

  Authors: Sebastian Joyce, Luc Van Kaer

  Nature medicine. 07/2008; 14(6):609-10.

• Invariant natural killer T cells trigger adaptive lymphocytes to churn up bile.

  Authors: Sebastian Joyce, Luc Van Kaer

  Cell host & microbe. 06/2008; 3(5):275-7.

  How innate immune response causes autoimmunity has remained an enigma. In this issue of Cell Host & Microbe, Mattner et al. demonstrate that invariant natural killer T cells activated by the mucosalHow innate immune response causes autoimmunity has remained an enigma. In this issue of Cell Host & Microbe, Mattner et al. demonstrate that invariant natural killer T cells activated by the mucosal commensal Novosphingobium aromaticivorans precipitate chronic T cell-mediated autoimmunity against small bile ducts that mirrors human primary biliary cirrhosis. These findings provide a mechanistic understanding of the role of innate immunity toward a microbe in the development of autoimmunity.

• CD1d-restricted glycolipid antigens: presentation principles, recognition logic and functional consequences.

  Authors: William C Florence, Rakesh K Bhat, Sebastian Joyce

  Expert reviews in molecular medicine. 02/2008; 10:e20.

  Invariant natural killer T (iNKT) cells are innate lymphocytes whose functions are regulated by self and foreign glycolipid antigens presented by the antigen-presenting molecule CD1d. Activation ofInvariant natural killer T (iNKT) cells are innate lymphocytes whose functions are regulated by self and foreign glycolipid antigens presented by the antigen-presenting molecule CD1d. Activation of iNKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers and self-antigens. The nature of CD1d-restricted antigens, the manner in which they are recognised and the unique effector functions of iNKT cells suggest an innate immunoregulatory role for this subset of T cells. Their ability to respond fast and our ability to steer iNKT cell cytokine response to altered lipid antigens make them an important target for vaccine design and immunotherapies against autoimmune diseases. This review summarises our current understanding of CD1d-restricted antigen presentation, the recognition of such antigens by an invariant T-cell receptor on iNKT cells, and the functional consequences of these interactions.

• A Staphylococcus aureus regulatory system that responds to host heme and modulates virulence.

  Authors: Victor J Torres, Devin L Stauff, Gleb Pishchany, Jelena S Bezbradica, Laura E Gordy, Juan Iturregui, Kelsi L Anderson, Paul M Dunman, Sebastian Joyce, Eric P Skaar

  Cell host & microbe. 05/2007; 1(2):109-19.

  Staphylococcus aureus, a bacterium responsible for tremendous morbidity and mortality, exists as a harmless commensal in approximately 25% of humans. Identifying the molecular machinery activatedStaphylococcus aureus, a bacterium responsible for tremendous morbidity and mortality, exists as a harmless commensal in approximately 25% of humans. Identifying the molecular machinery activated upon infection is central to understanding staphylococcal pathogenesis. We describe the heme sensor system (HssRS) that responds to heme exposure and activates expression of the heme-regulated transporter (HrtAB). Inactivation of the Hss or Hrt systems leads to increased virulence in a vertebrate infection model, a phenotype that is associated with an inhibited innate immune response. We suggest that the coordinated activity of Hss and Hrt allows S. aureus to sense internal host tissues, resulting in tempered virulence to avoid excessive host tissue damage. Further, genomic analyses have identified orthologous Hss and Hrt systems in Bacillus anthracis, Listeria monocytogenes, and Enterococcus faecalis, suggesting a conserved regulatory system by which Gram-positive pathogens sense heme as a molecular marker of internal host tissue and modulate virulence.

• Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny.

  Authors: Jelena S Bezbradica, Laura E Gordy, Aleksandar K Stanic, Srdjan Dragovic, Timothy Hill, Jacek Hawiger, Derya Unutmaz, Luc Van Kaer, Sebastian Joyce

  Immunity. 10/2006; 25(3):487-97.

  Invariant natural killer T (iNKT) cell-derived cytokines have important functions in inflammation, host defense, and immunoregulation. Yet, when and how iNKT cells undergo effector differentiation,Invariant natural killer T (iNKT) cell-derived cytokines have important functions in inflammation, host defense, and immunoregulation. Yet, when and how iNKT cells undergo effector differentiation, which endows them with the capacity to rapidly secrete cytokines upon activation, remains unknown. We discovered that granulocyte-macrophage colony-stimulating factor (Csf-2)-deficient mice developed iNKT cells that failed to respond to the model antigen alpha-galactosylceramide because of an intrinsic defect in the fusion of secretory vesicles with the plasma membrane. Exogenous Csf-2 corrected the functional defect only when supplied during the development of thymic, but not mature, splenic Csf-2-deficient iNKT cells. Thus, we ascribe a unique function to Csf-2, which regulates iNKT cell effector differentiation during development by a mechanism that renders them competent for cytokine secretion.

• Viral evasion of antigen presentation: not just for peptides anymore.

  Authors: Luc Van Kaer, Sebastian Joyce

  Nature immunology. 09/2006; 7(8):795-7.

• Characterization and functional analysis of mouse invariant natural T (iNKT) cells.

  Authors: Jelena S Bezbradica, Aleksandar K Stanic, Sebastian Joyce

  Current protocols in immunology / edited by John E. Coligan ... [et al.]. 08/2006; Chapter 14:Unit 14.13.

  Invariant natural T (iNKT) cells are innate lymphocytes that recognize CD1d-restricted lipid antigens and have immunoregulatory properties. Human and mouse CD1d-restricted glycolipid antigen(s) andInvariant natural T (iNKT) cells are innate lymphocytes that recognize CD1d-restricted lipid antigens and have immunoregulatory properties. Human and mouse CD1d-restricted glycolipid antigen(s) and the iNKT cell functions they elicit are highly conserved, whereby, making the mouse an excellent animal model for understanding iNKT cell biology in vivo. This unit describes basic methods for the characterization and quantification (see Basic Protocol 1) and functional analysis of murine iNKT cells in vivo or in vitro (see Basic Protocols 2, 3, and 4). This unit also contains protocols that describe enrichment of iNKT cells (see Support Protocol 1), generation of CD1d-tetramer (see Support Protocol 2), and lipid antigen loading on cell-bound (see Support Protocol 3) or soluble (see Support Protocol 3) CD1d.