Peter Cresswell, Ph.D.

Professor of Immunobiology and Cell Biology and Dermatology Investigator, Howard Hughes Medical Institute
Cresswell lab website Phone: (203) 785-5176 Lab: (203) 737-2452 Assistant: (203) 785-5176 Fax: (203) 785-4461 e-mail: peter.cresswell@yale.edu		Section of Immunobiology Yale University School of Medicine 300 Cedar Street P.O. Box 208011 New Haven, CT 06520-8011 <Courier Address> 300 Cedar Street, TAC S669/670 New Haven, CT 06519-1612

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The major interest of this laboratory is in unraveling the molecular details of antigen processing, defined as the mechanisms regulating the association of MHC and related molecules with their ligands to generate the complexes recognized by T lymphocytes.

MHC class I molecules in the endoplasmic reticulum (ER) bind peptides translocated from the cytosol by the Transporters associated with Antigen Processing (TAP). Peptide binding to class I molecules occurs while they are associated with the Peptide Loading Complex (PLC), a multi subunit assembly containing calreticulin, the thiol oxido-reductase ERp57 stably disulfide-linked to an MHC-encoded membrane glycoprotein called tapasin, and TAP. The tapasin-ERp57 conjugate recruits class I molecules and associated calreticulin to the PLC and facilitates peptide loading by the class I molecules, editing the pool of bound peptides to maximize their affinity.

MHC class II molecules form a nine chain complex in the ER, with three ab dimers associated with a trimer of the invariant chain. After invariant chain degradation in the endocytic pathway, a residual invariant chain fragment is catalytically eliminated by an MHC-encoded glycoprotein, HLA-DM, liberating the peptide binding site of the class II molecule. Peptides or large fragments of protein can bind and linearization of folded proteins by reduction of disulfide bonds, mediated by a gamma interferon-inducible lysosomal thiol reductase (GILT), is important for this process.

CD1 molecules are similar to class I molecules but bind lipids rather than peptides. Current data suggests that CD1d molecules bind lipids both in the endoplasmic reticulum and endocytic pathway.  Binding of lipids in the endocytic pathway is catalysed by saposins, small lipid transfer proteins originally identified as essential cofactors for sphingolipid degradation. Saposin B is the key saposin involved in facilitating lipid association with CD1d. CD1d-lipid complexes are recognized by NKT cells, and the importance of such recognition is underscored by the observation that Herpes simplex virus-1 infection induces the down-regulation of CD1d molecules from the surface of infected cells.

Other work centers on studies of the antiviral mechanisms of proteins inducible by Type 1 and Type 2 interferons. One such protein, viperin, mediates resistance to infection by influenza virus and human cytomegalovirus. The step in the viral life cycle affected by viperin is the final stage, namely budding and release from the plasma membrane.

 

CLASS II/GILT

 

 

Selected Publications

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Yuan, W., Qi, X., Psang, P., Kang, S-K., Illarionov, P.A., Besra, G.S., Gumperz, J., Cresswell, P.  Saposin B is the dominant sapsosin that facilitates lipid binding to human CD1d molecules.  Proc. Natl. Acad. Sci. 104: 5551-5556, 2007.
Paduraru, C., Spiridon, L., Yuan, W., Bricard, G., Valencia, X., Porcelli, S.A., Illarionov, P.A., Besra, G.S., Petrescu, S.M., Petrescu, A-J., Cresswell, P.  An N-linked glycan modulates the interaction between the CD1d heavy chain and b2-microglobulin.  J. Biol. Chem. 281(52):40369-40378, 2006.

Yuan, W., Dasgupta, A., Cresswell, P.  Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling.  Nat. Immunol., 7(8):835-842, 2006.

Hastings Taraszka K., Lackman, R.L., Cresswell, P.  Functional requirements for the lysosomal thiol reductase GILT in MHC class II-restricted antigen processing.  J. Immunol. 177:8569-8577.
Ackerman, A.L., Giodini, A., Cresswell, P.  A role for the endoplasmic reticulum protein retrotranslocation machinery during crosspresentation by dendritic cells.  Immunity 25(4):523-525, 2006.

Lackman, R., Cresswell, P.  Exposure of the promonocytic cell line THP-1 to Escherichia coli induces IFN-g-inducible lysosomal thiol reductase expression by inflammatory cytokines.  J. Immunol. 177:4833-4840, 2006.

Shen, H., Ackerman, A.L., Cody, V., Giodini, A., Hinson, E.R., Cresswell, P., Edelson, R.L., Saltzman, W.M., Hanlon, D.J.  Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles.  Immunology 117:78-88, 2006.

Peaper, D., Wearsch, P.A., Cresswell, P.  Tapasin and ERp57 form a stable disulfide-linked dimer within the MHC class I peptide-loading complex.  EMBO J., 24(20):3613-3623, 2005.

Cresswell, P., Ackerman, A.L., Giodini, A., Peaper, D.R., Wearsch, P.A.  Mechanisms of MHC class I-restricted antigen processing and cross presentation.  Immunol. Rev. 207:145-157, 2005.

Cresswell, P.  Antigen processing and presentation.  Immunol. Rev. 207:5-7, 2005.

Modiano, N., Lu, Y.E., Cresswell, P.  Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN--inducible cofactor.  Proc. Natl. Acad. Sci. 102(24), 8680-8685, 2005.

Bangia, N., Cresswell, P.  Stoichiometric tapasin interactions in the catalysis of major histocompatibility complex class I molecule assembly.  Immunol. 114:346-353, 2005.

Ackerman, A.L., Kyritsis, C., Tampé, R., Cresswell, P.  Access of soluble antigens to the endoplasmic reticulum can explain cross presentation by dendritic cells.  Nat. Immunol. 6(1):107-113, 2005.