Biology; Cell Biology; Endoplasmic Reticulum; Immunity; Major Histocompatibility Complex
Molecular Virology: Virology Laboratories
Rheumatic Diseases Research Core
MHC class I molecules in the endoplasmic reticulum (ER) bind antigenic peptides translocated from the cytosol by the Transporters associated with Antigen Processing (TAP). The assembly of a class I molecule involves two chaperones, calnexin and calreticulin, and the thiol oxido-reductase, ERp57. Calreticulin- and ERp57-associated class I molecules physically associate with TAP molecules, with another protein, tapasin, serving as a bridge. Peptide binding releases the class I molecules from the “peptide loading complex”, and a disulfide-linked dimer of tapasin and ERp57 within the complex catalyzes peptide loading. The peptides can come from extracellular proteins in the case of dendritic cells, a process called cross-presentation. Calnexin, calreticulin and ERp57 are also involved in the assembly of CD1d molecules, which bind lipids.
MHC class II molecules form a complex in the ER with the invariant chain. This complex is targeted to lysosomes where invariant chain is degraded and a residual fragment eliminated by HLA-DM, allowing peptide binding. A gamma interferon-inducible lysosomal thiol reductase (GILT) plays a role in peptide generation, shown using a GILT “knock-out” mouse. Reduction of disulfide bonds by GILT helps unfold protein antigens to MHC class II molecules. Recent work has shown that cross-presentation of disulfide-containing antigens can be facilitated by GILT.
Other work centers on antiviral mechanisms of proteins inducible by interferons. The interferon-inducible viperin protein plays a role in resistance to influenza virus.
Specialized Terms: Molecular mechanisms of antigen processing; Assembly and intracellular transport of CD1 molecules, Class I and Class II MHC molecules; Effector functions; mechanisms of action of interferon-induced proteins; Viral immunity
Extensive Research Description
The main interests of this laboratory are in two areas; antigen processing and the mechanisms of action of antiviral proteins stimulated by interferons. Studies of MHC class I molecules center onto problems. The first is the mechanism(s) governing the association of antigen-derived peptides with class I molecules in the endoplasmic reticulum (ER). Peptides are transported into the ER by the Transporter associated with Antigen Processing (TAP) after their generation from cytosolic proteins by proteasomal degradation. Peptide binding occurs in the context of the peptide loading complex, which consists of TAP, an associated transmembrane glycoprotein called tapasin, and an associated 'empty' class I molecule which is a heterodimer of the class I heavy chain and ß2microglobulin. Also in the complex are two housekeeping molecules, the chaperone calreticulin which associates with the glycan on the class I heavy chain, and ERp57, a thiol oxidoreductase that is disulfide linked to tapasin. How the peptide loading complex promotes peptide loading of class I molecules at the molecular level is under intensive investigation, but it is clear that the tapasin-ERp57 heterodimer is critically involved in peptide binding and the process of peptide editing, which ensures that MHC class I molecules associate with peptides of the highest affinity before leaving the ER for the cell surface.
The second area of interest in MHC class I lies in the phenomenon of cross-presentation, which is essential for priming the response of naïve CD8-positive T cells to viral antigens in vivo. Cross-presentation is a particular property of dendritic cells that allows them to generate MHC class I complexes with peptides derived from protein antigens that are internalized by phagocytosis or pinocytosis. These two processes ultimately allow entry of external proteins into the cytosol, either by crossing the phagosomal membrane or the ER membrane after they gain access to the ER. The mechanisms allowing protein access to the ER and the translocation mechanism responsible for entry into the cytosol are two problems being studied. Recent work shows that unfolding of the antigenic protein in the endocytic pathway facilitates its translocation into the cytosol. If the protein contains disulfide bonds reduction by Gamma interferon-inducible lysosomal thiol reductase (GILT) may be required.
Work on MHC class II currently focuses on the role of GILT in MHC class II-restricted antigen processing. The latter is important for the recognition by CD4-positive T cells of protein antigens containing disulfide bonds, demonstrated in a GILT knockout mouse.
A third area of interest within the antigen processing field centers on CD1d molecules, which are structurally similar to MHC class I molecules but bind lipids rather than peptides. We are trying to understand the role of lipid binding and of ER chaperones in the assembly of CD1 molecules, as well as the precise mechanisms governing lipid binding in endosomes and lysosomes. We have shown that saposins, small molecules essential for the degradation of sphingolipids, are required for lipid binding to CD1d molecules in the endocytic pathway. Saposins are capable of mobilizing monomeric lipid molecules from the endosomal or lysosomal bilayer which then allows them to bind to theCD1d molecules. The importance of CD1d in antiviral responses is highlighted by the efforts made by a number of viruses to reduce CD1dexpression upon infection. We found that Herpes simplexvirus-1 (HSV-1) does this by inhibiting CD1d re-expression on the surface of cells during recycling through the endosomal/lysosomal system. Upon HSV-1 infection, CD1d molecules accumulate in lysosomes and disappear from the cell surface.
Finally, we are interested in understanding the functions of interferon-inducible proteins, particularly a protein we identified and called viperin which inhibits the growth of a number of viruses, including influenza virus. We originally showed that viperin has an inhibitory effect on the growth of human cytomegalovirus (CMV), even though it is induced by CMV upon infection. We have recently shown that viperin is relocalized by a CMV-encoded protein to mitochondria, where it has an effect on cellular metabolism that facilitates CMV replication.
Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer.
Dong G, Wearsch PA, Peaper DR, Cresswell P, Reinisch KM. Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer. Immunity 2009, 30:21-32.
Defective cross-presentation of viral antigens in GILT-free mice.
Singh R, Cresswell P. Defective cross-presentation of viral antigens in GILT-free mice. Science (New York, N.Y.) 2010, 328:1394-8.
Full List of PubMed Publications
- Arshad N, Cresswell P: Tumor-associated calreticulin variants functionally compromise the peptide loading complex and impair its recruitment of MHC-I. J Biol Chem. 2018 May 16; 2018 May 16. PMID: 29769311
- Cresswell P: Editing peptide presentation to T cells. Science. 2017 Nov 24. PMID: 29170218
- Grotzke JE, Kozik P, Morel JD, Impens F, Pietrosemoli N, Cresswell P, Amigorena S, Demangel C: Sec61 blockade by mycolactone inhibits antigen cross-presentation independently of endosome-to-cytosol export. Proc Natl Acad Sci U S A. 2017 Jul 18; 2017 Jul 5. PMID: 28679634
- Fenwick MK, Li Y, Cresswell P, Modis Y, Ealick SE: Structural studies of viperin, an antiviral radical SAM enzyme. Proc Natl Acad Sci U S A. 2017 Jun 27; 2017 Jun 12. PMID: 28607080
- Cresswell P, Roche PA: Editorial Overview: Antigen Processing and Presentation; many fingers in many pies. Curr Opin Immunol. 2017 Jun; 2017 Jul 14. PMID: 28716443
- Grotzke JE, Sengupta D, Lu Q, Cresswell P: The ongoing saga of the mechanism(s) of MHC class I-restricted cross-presentation. Curr Opin Immunol. 2017 Jun; 2017 May 18. PMID: 28528219
- Hee JS, Cresswell P: Viperin interaction with mitochondrial antiviral signaling protein (MAVS) limits viperin-mediated inhibition of the interferon response in macrophages. PLoS One. 2017; 2017 Feb 16. PMID: 28207838
- Grotzke JE, Cresswell P: Are ERAD components involved in cross-presentation? Mol Immunol. 2015 Dec; 2015 May 23. PMID: 26005101
- He P, Grotzke JE, Ng BG, Gunel M, Jafar-Nejad H, Cresswell P, Enns GM, Freeze HH: A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts. Glycobiology. 2015 Aug; 2015 Apr 21. PMID: 25900930
- Samie M, Cresswell P: The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways. Nat Immunol. 2015 Jul; 2015 Jun 1. PMID: 26030023
- Cresswell P, Roche PA: Invariant chain-MHC class II complexes: always odd and never invariant. Immunol Cell Biol. 2014 Jul; 2014 Apr 29. PMID: 24777311
- Wagner CS, Grotzke J, Cresswell P: Intracellular regulation of cross-presentation during dendritic cell maturation. PLoS One. 2013; 2013 Oct 3. PMID: 24098562
- Kunte A, Zhang W, Paduraru C, Veerapen N, Cox LR, Besra GS, Cresswell P: Endoplasmic reticulum glycoprotein quality control regulates CD1d assembly and CD1d-mediated antigen presentation. J Biol Chem. 2013 Jun 7; 2013 Apr 24. PMID: 23615906
- Leonhardt RM, Vigneron N, Hee JS, Graham M, Cresswell P: Critical residues in the PMEL/Pmel17 N-terminus direct the hierarchical assembly of melanosomal fibrils. Mol Biol Cell. 2013 Apr; 2013 Feb 6. PMID: 23389629
- Paduraru C, Bezbradica JS, Kunte A, Kelly R, Shayman JA, Veerapen N, Cox LR, Besra GS, Cresswell P: Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition. Proc Natl Acad Sci U S A. 2013 Mar 26; 2013 Mar 14. PMID: 23493550
- Grotzke JE, Lu Q, Cresswell P: Deglycosylation-dependent fluorescent proteins provide unique tools for the study of ER-associated degradation. Proc Natl Acad Sci U S A. 2013 Feb 26; 2013 Feb 11. PMID: 23401531
- West LC, Cresswell P: Expanding roles for GILT in immunity. Curr Opin Immunol. 2013 Feb; 2012 Dec 12. PMID: 23246037
- Wearsch PA, Cresswell P: In vitro reconstitution of the MHC class I peptide-loading complex. Methods Mol Biol. 2013. PMID: 23329479
- West LC, Grotzke JE, Cresswell P: MHC class II-restricted presentation of the major house dust mite allergen Der p 1 Is GILT-dependent: implications for allergic asthma. PLoS One. 2013; 2013 Jan 11. PMID: 23326313
- Seo JY, Cresswell P: Viperin regulates cellular lipid metabolism during human cytomegalovirus infection. PLoS Pathog. 2013; 2013 Aug 1. PMID: 23935494
- Panter MS, Jain A, Leonhardt RM, Ha T, Cresswell P: Dynamics of major histocompatibility complex class I association with the human peptide-loading complex. J Biol Chem. 2012 Sep 7; 2012 Jul 24. PMID: 22829594
- Bergman CM, Marta CB, Maric M, Pfeiffer SE, Cresswell P, Ruddle NH: A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-γ-inducible lysosomal thiol reductase-free mice. J Immunol. 2012 Jun 15; 2012 May 14. PMID: 22586035
- Wagner CS, Grotzke JE, Cresswell P: Intracellular events regulating cross-presentation. Front Immunol. 2012; 2012 Jun 4. PMID: 22675326
- Shenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P, MacMicking JD: GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science. 2012 Apr 27; 2012 Mar 29. PMID: 22461501
- Wagner CS, Cresswell P: TLR and nucleotide-binding oligomerization domain-like receptor signals differentially regulate exogenous antigen presentation. J Immunol. 2012 Jan 15; 2011 Dec 9. PMID: 22156493
- Seo JY, Yaneva R, Cresswell P: Viperin: a multifunctional, interferon-inducible protein that regulates virus replication. Cell Host Microbe. 2011 Dec 15. PMID: 22177558
- Seo JY, Yaneva R, Hinson ER, Cresswell P: Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity. Science. 2011 May 27; 2011 Apr 28. PMID: 21527675
- Wearsch PA, Peaper DR, Cresswell P: Essential glycan-dependent interactions optimize MHC class I peptide loading. Proc Natl Acad Sci U S A. 2011 Mar 22; 2011 Mar 7. PMID: 21383180
- Zhang W, Wearsch PA, Zhu Y, Leonhardt RM, Cresswell P: A role for UDP-glucose glycoprotein glucosyltransferase in expression and quality control of MHC class I molecules. Proc Natl Acad Sci U S A. 2011 Mar 22; 2011 Mar 7. PMID: 21383159
- Leonhardt RM, Vigneron N, Rahner C, Cresswell P: Proprotein convertases process Pmel17 during secretion. J Biol Chem. 2011 Mar 18; 2011 Jan 19. PMID: 21247888
- Zhu Y, Zhang W, Veerapen N, Besra G, Cresswell P: Calreticulin controls the rate of assembly of CD1d molecules in the endoplasmic reticulum. J Biol Chem. 2010 Dec 3; 2010 Sep 22. PMID: 20861015
- Singh R, Cresswell P: Defective cross-presentation of viral antigens in GILT-free mice. Science. 2010 Jun 11. PMID: 20538950
- Leonhardt RM, Vigneron N, Rahner C, Van den Eynde BJ, Cresswell P: Endoplasmic reticulum export, subcellular distribution, and fibril formation by Pmel17 require an intact N-terminal domain junction. J Biol Chem. 2010 May 21; 2010 Mar 15. PMID: 20231267
- Hinson ER, Joshi NS, Chen JH, Rahner C, Jung YW, Wang X, Kaech SM, Cresswell P: Viperin is highly induced in neutrophils and macrophages during acute and chronic lymphocytic choriomeningitis virus infection. J Immunol. 2010 May 15; 2010 Apr 21. PMID: 20410488
- Hinson ER, Cresswell P: The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic alpha-helix. Proc Natl Acad Sci U S A. 2009 Dec 1; 2009 Nov 17. PMID: 19920176
- Vigneron N, Peaper DR, Leonhardt RM, Cresswell P: Functional significance of tapasin membrane association and disulfide linkage to ERp57 in MHC class I presentation. Eur J Immunol. 2009 Sep. PMID: 19701894
- Yuan W, Kang SJ, Evans JE, Cresswell P: Natural lipid ligands associated with human CD1d targeted to different subcellular compartments. J Immunol. 2009 Apr 15. PMID: 19342656
- Giodini A, Rahner C, Cresswell P: Receptor-mediated phagocytosis elicits cross-presentation in nonprofessional antigen-presenting cells. Proc Natl Acad Sci U S A. 2009 Mar 3; 2009 Feb 13. PMID: 19218463
- Hinson ER, Cresswell P: The N-terminal amphipathic alpha-helix of viperin mediates localization to the cytosolic face of the endoplasmic reticulum and inhibits protein secretion. J Biol Chem. 2009 Feb 13; 2008 Dec 12. PMID: 19074433
- Dong G, Wearsch PA, Peaper DR, Cresswell P, Reinisch KM: Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer. Immunity. 2009 Jan 16. PMID: 19119025
- Wearsch PA, Cresswell P: The quality control of MHC class I peptide loading. Curr Opin Cell Biol. 2008 Dec; 2008 Oct 29. PMID: 18926908
- Singh R, Jamieson A, Cresswell P: GILT is a critical host factor for Listeria monocytogenes infection. Nature. 2008 Oct 30; 2008 Sep 24. PMID: 18815593
- Peaper DR, Cresswell P: The redox activity of ERp57 is not essential for its functions in MHC class I peptide loading. Proc Natl Acad Sci U S A. 2008 Jul 29; 2008 Jul 23. PMID: 18650385
- Giodini A, Cresswell P: Hsp90-mediated cytosolic refolding of exogenous proteins internalized by dendritic cells. EMBO J. 2008 Jan 9; 2007 Nov 29. PMID: 18046456
- Peaper DR, Cresswell P: Regulation of MHC class I assembly and peptide binding. Annu Rev Cell Dev Biol. 2008. PMID: 18729726
- Leonhardt RM, Lee SJ, Kavathas PB, Cresswell P: Severe tryptophan starvation blocks onset of conventional persistence and reduces reactivation of Chlamydia trachomatis. Infect Immun. 2007 Nov; 2007 Aug 27. PMID: 17724071
- Stepensky D, Bangia N, Cresswell P: Aggregate formation by ERp57-deficient MHC class I peptide-loading complexes. Traffic. 2007 Nov; 2007 Sep 6. PMID: 17822402
- Lackman RL, Jamieson AM, Griffith JM, Geuze H, Cresswell P: Innate immune recognition triggers secretion of lysosomal enzymes by macrophages. Traffic. 2007 Sep; 2007 Jun 6. PMID: 17555533
- Wang X, Hinson ER, Cresswell P: The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe. 2007 Aug 16. PMID: 18005724
- Wearsch PA, Cresswell P: Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer. Nat Immunol. 2007 Aug; 2007 Jul 1. PMID: 17603487
- Yuan W, Qi X, Tsang P, Kang SJ, Illarionov PA, Besra GS, Gumperz J, Cresswell P: Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules. Proc Natl Acad Sci U S A. 2007 Mar 27; 2007 Mar 19. PMID: 17372201
- Paduraru C, Spiridon L, Yuan W, Bricard G, Valencia X, Porcelli SA, Illarionov PA, Besra GS, Petrescu SM, Petrescu AJ, Cresswell P: An N-linked glycan modulates the interaction between the CD1d heavy chain and beta 2-microglobulin. J Biol Chem. 2006 Dec 29; 2006 Oct 27. PMID: 17071611
- Hastings KT, Lackman RL, Cresswell P: Functional requirements for the lysosomal thiol reductase GILT in MHC class II-restricted antigen processing. J Immunol. 2006 Dec 15. PMID: 17142755
- Ackerman AL, Giodini A, Cresswell P: A role for the endoplasmic reticulum protein retrotranslocation machinery during crosspresentation by dendritic cells. Immunity. 2006 Oct; 2006 Oct 5. PMID: 17027300
- Lackman RL, Cresswell P: Exposure of the promonocytic cell line THP-1 to Escherichia coli induces IFN-gamma-inducible lysosomal thiol reductase expression by inflammatory cytokines. J Immunol. 2006 Oct 1. PMID: 16982925
- Yuan W, Dasgupta A, Cresswell P: Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling. Nat Immunol. 2006 Aug; 2006 Jul 16. PMID: 16845396
- Shen H, Ackerman AL, Cody V, Giodini A, Hinson ER, Cresswell P, Edelson RL, Saltzman WM, Hanlon DJ: Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles. Immunology. 2006 Jan. PMID: 16423043
- Peaper DR, Wearsch PA, Cresswell P: Tapasin and ERp57 form a stable disulfide-linked dimer within the MHC class I peptide-loading complex. EMBO J. 2005 Oct 19; 2005 Sep 29. PMID: 16193070
- Cresswell P, Ackerman AL, Giodini A, Peaper DR, Wearsch PA: Mechanisms of MHC class I-restricted antigen processing and cross-presentation. Immunol Rev. 2005 Oct. PMID: 16181333
- Cresswell P: Antigen processing and presentation. Immunol Rev. 2005 Oct. PMID: 16181322
- Modiano N, Lu YE, Cresswell P: Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor. Proc Natl Acad Sci U S A. 2005 Jun 14; 2005 Jun 3. PMID: 15937107
- Ackerman AL, Kyritsis C, Tampé R, Cresswell P: Access of soluble antigens to the endoplasmic reticulum can explain cross-presentation by dendritic cells. Nat Immunol. 2005 Jan; 2004 Dec 12. PMID: 15592474
- Ackerman AL, Cresswell P: Cellular mechanisms governing cross-presentation of exogenous antigens. Nat Immunol. 2004 Jul. PMID: 15224093
- Wearsch PA, Jakob CA, Vallin A, Dwek RA, Rudd PM, Cresswell P: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin independently of their assembly status. J Biol Chem. 2004 Jun 11; 2004 Mar 31. PMID: 15056662
- Cresswell P: Cell biology. Cutting and pasting antigenic peptides. Science. 2004 Apr 23. PMID: 15105483
- Kang SJ, Cresswell P: Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Nat Immunol. 2004 Feb; 2004 Jan 11. PMID: 14716312
- Ackerman AL, Kyritsis C, Tampé R, Cresswell P: Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens. Proc Natl Acad Sci U S A. 2003 Oct 28; 2003 Oct 15. PMID: 14561893
- Ackerman AL, Cresswell P: Regulation of MHC class I transport in human dendritic cells and the dendritic-like cell line KG-1. J Immunol. 2003 Apr 15. PMID: 12682250
- Kang SJ, Cresswell P: Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain. J Biol Chem. 2002 Nov 22; 2002 Sep 17. PMID: 12239218
- Phan UT, Lackman RL, Cresswell P: Role of the C-terminal propeptide in the activity and maturation of gamma -interferon-inducible lysosomal thiol reductase (GILT). Proc Natl Acad Sci U S A. 2002 Sep 17; 2002 Aug 27. PMID: 12198183
- Kang SJ, Cresswell P: Regulation of intracellular trafficking of human CD1d by association with MHC class II molecules. EMBO J. 2002 Apr 2. PMID: 11927549
- Dick TP, Bangia N, Peaper DR, Cresswell P: Disulfide bond isomerization and the assembly of MHC class I-peptide complexes. Immunity. 2002 Jan. PMID: 11825568
- Dick TP, Cresswell P: Thiol oxidation and reduction in major histocompatibility complex class I-restricted antigen processing and presentation. Methods Enzymol. 2002. PMID: 11885293
- Phan UT, Maric M, Cresswell P: Disulfide reduction in major histocompatibility complex class II-restricted antigen processing by interferon-gamma-inducible lysosomal thiol reductase. Methods Enzymol. 2002. PMID: 11885292