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One or more keywords matched the following properties of Stern, Lawrence

Academic Background


    B. A. cum laude Chemistry Cornell University (1983)
    Ph. D. Biochemistry Massachusetts Institute of Technology (1989)

Professional Experience:

    Assistant (1994-1999 ) and Associate (1999-2002) Professor of Chemistry
    Member, Center for Biomedical Engineering (1997-2002),
    Massachusetts Institute of Technology
    Structure and Function of Immune Receptors

    Postdoctoral Fellow with Don. C. Wiley (1989-1994)
    Harvard University, Department of Biochemistry & Molecular Biology
    Structure of Major Histocompatibility Proteins

    Graduate Research Assistant with H. Gobind Khorana, (1983-1989)
    Massachusetts Institute of Technology, Department of Chemistry
    Structure-Function Studies of Bacteriorhodopsin

    Research Student with Lawrence Que, Jr. (1981-1983)
    Cornell University, Department of Chemistry
    Mechanistic Studies of Catechol Di-oxygenases

Molecular recognition in the immune system

Photo: Lawrence J. Stern, PhDMy primary research interest is in the biochemical processes that underlie cellular recognition and signaling. Research in my laboratory has concentrated on the immune system, because of its intrinsic importance to human health and disease, and because of its treasure of biochemical mechanisms by which cells communicate with their environment and with each other. Our approach combines in vitro biophysical and biochemical studies of the proteins involved in these processes, with cellular studies of their functions and intermolecular interactions. We have focus on two related areas: antigen presentation by MHC proteins, and the molecular mechanisms of T cell activation.

Antigen presentation by MHC proteins

A key feature of immune recognition is the interaction of proteins encoded by the Major Histocompatibility Complex (MHC) with antibody-like receptors on T cells. MHC proteins bind peptide antigens within the cell, and display them at the cell surface for interaction with T cell receptors. MHC proteins are highly polymorphic, with allelic differences associated with differences in peptide binding preferences and in individual susceptibility to allergy, infection, and autoimmune disease. We study MHC proteins and their interactions with peptides through a combination of biophysical and cellular analysis. The crystal structure of an MHC-peptide complex revealed that peptides of completely different sequence can be accommodated in the site with almost no alteration of the MHC molecule, with binding specificity determined by subtle details of interactions in the side-chain binding pockets. Hydrodynamic, enzymatic, and spectroscopic studies have identified a peptide-dependent conformational change, in which the region ß58-69 of the MHC protein folds over the bound peptide to trap it in the site, in the rate determining step for the overall peptide binding reaction. In continuing studies, we are investigating the mechanism of peptide-exchange catalysis by DM, a major unsolved problem with implications to other systems in which structural homologues function as chaperones or conformational catalysis. In cellular studies, we have discovered a new extracellular pathway for antigen presentation particularly active in immature dendritic cells, in which peptide generation and MHC loading occur entirely outside of the cell. This pathway may help to explain the unique antigen presentation abilities of dendritic cells, particularly their role in maintaining peripheral tolerance to self-antigens. Recently we have observed that this process occurs also in microglia, enigmatic brain cells involved in immune tolerance and response to infection.

T cell activation

The interaction of MHC-peptide complexes on the surface of an antigen presenting cell with receptors on T cells induces characteristic T cell effector functions. Once activated, T cells play crucial roles in the initiation and control of the immune response to foreign material in the body, by killing infected cell and activating other immune system cells. The molecular events at the juxtaposed membranes of T cell and antigen presenting cell that trigger these cellular activation processes are unknown, but are believed to involve receptor aggregation or clustering. To approach the mechanism of aggregation-activated signaling in T cells, we developed a novel model system using chemically-defined oligomers of MHC-peptide complexes, and used them to determine the minimal requirements for T cell activation. For a given amount of receptor engagement, the extent of activation was equivalent for MHC dimers, trimers, tetramers, and octamers, but monomers were inactive, showing definitively that TCR dimerization was necessary and sufficient for activation. Using dimers with various topological constraints, we showed that that the activation trigger did not involve a ligand-induced allosteric change, as observed for many other dimerization-activated receptor systems, but rather a ligand-induced oligomerization. To investigate the molecular events by which oligomerization of ligand-binding domains communicates a signal into the cytoplasm, we have begun structure-function studies of TCR cytoplasmic domains implicated in signaling. We have found that the cytoplasmic domain of TCR zeta exhibits a lipid-dependent folding transition, which regulates accessibility to cytoplasmic protein kinases known to interact with engaged receptor. Based on these results we proposed a novel mechanism for coupling receptor clustering to signaling cascades through zeta subunit conformational changes. In addition to helping unravel the activation mechanism, MHC oligomers are proving to be very useful reagents to detect and identify specific CD4+ T cells present at low frequency in mixed populations in blood and other clinical samples. In continuing work we are probing the structure of receptor components, developing new methods to investigate the T cell activation trigger, and using MHC oligomers to detect antigen-specific T cells in malaria, influenza, and HIV infection.


Figure 1: Peptide structure

Figure 1: Structure of an antigenic peptide from influenza virus bound to the class IIMHC protein HLA-DR1. The MHC peptide binding domain is shown as a cyan surface,the influenza peptide as a CPK model. Antigen receptors on T cells bind to thiscomplex as part of the process that triggers an immune response. The structureand function of MHC proteins, and the cellular pathways by which they are loaded,are a focus of study in the Stern laboraotry.

Figure 2: Interaction model

Figure 2. Model for the interaction of an MHC-peptide complexon one cell with a T cell receptor on another cell. Recognitionof foreign MHC-peptide complexes activates the T cells to killthe presenting cell or to recruit other immune cells to the vicinity.The triggering process involves clustering or aggregation ofTCR on the T cell surface. Determination of the molecularmechanism of such clustering-induced signaling is anotherfocus of research in the Stern Laboratory.

One or more keywords matched the following items that are connected to Stern, Lawrence
Item TypeName
Academic Article Exploration of the P6/P7 region of the peptide-binding site of the human class II major histocompatability complex protein HLA-DR1.
Academic Article A polymorphic pocket at the P10 position contributes to peptide binding specificity in class II MHC proteins.
Academic Article Antagonism of HIV-specific CD4+ T cells by C-terminal truncation of a minimum epitope.
Academic Article CD8 T cells, like CD4 T cells, are triggered by multivalent engagement of TCRs by MHC-peptide ligands but not by monovalent engagement.
Academic Article Major histocompatibility complex and T cell interactions of a universal T cell epitope from Plasmodium falciparum circumsporozoite protein.
Academic Article GMCSF in the absence of other cytokines sustains human dendritic cell precursors with T cell regulatory activity and capacity to differentiate into functional dendritic cells.
Academic Article Vaccinia peptides eluted from HLA-DR1 isolated from virus-infected cells are recognized by CD4+ T cells from a vaccinated donor.
Academic Article Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression.
Academic Article HLA-DR: molecular insights and vaccine design.
Academic Article Peptide-MHC cellular microarray with innovative data analysis system for simultaneously detecting multiple CD4 T-cell responses.
Academic Article Mapping the HLA-DO/HLA-DM complex by FRET and mutagenesis.
Academic Article HLA-DM constrains epitope selection in the human CD4 T cell response to vaccinia virus by favoring the presentation of peptides with longer HLA-DM-mediated half-lives.
Academic Article Labeling antigen-specific CD4(+) T cells with class II MHC oligomers.
Academic Article Enhanced catalytic action of HLA-DM on the exchange of peptides lacking backbone hydrogen bonds between their N-terminal region and the MHC class II alpha-chain.
Academic Article Monoclonal antibodies specific for the empty conformation of HLA-DR1 reveal aspects of the conformational change associated with peptide binding.
Academic Article A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition.
Academic Article HLA-restricted epitope identification and detection of functional T cell responses by using MHC-peptide and costimulatory microarrays.
Academic Article Conformational variation of surface class II MHC proteins during myeloid dendritic cell differentiation accompanies structural changes in lysosomal MIIC.
Academic Article Probing the ligand-induced conformational change in HLA-DR1 by selective chemical modification and mass spectrometric mapping.
Academic Article MHC class II compartment subtypes: structure and function.
Academic Article Crystallographic structure of the human leukocyte antigen DRA, DRB3*0101: models of a directional alloimmune response and autoimmunity.
Academic Article Human cytotoxic CD4+ T cells recognize HLA-DR1-restricted epitopes on vaccinia virus proteins A24R and D1R conserved among poxviruses.
Academic Article Characterizing MHC-associated peptides by mass spectrometry.
Academic Article Human CD4+ T cell epitopes from vaccinia virus induced by vaccination or infection.
Academic Article Model for the peptide-free conformation of class II MHC proteins.
Academic Article An expanded self-antigen peptidome is carried by the human lymph as compared to the plasma.
Academic Article Conformational lability in the class II MHC 310 helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange.
Academic Article Human CD4+ T cell response to human herpesvirus 6.
Academic Article Minimal conformational plasticity enables TCR cross-reactivity to different MHC class II heterodimers.
Academic Article Conformational variation in structures of classical and non-classical MHCII proteins and functional implications.
Academic Article HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism.
Concept HLA-DR1 Antigen
Concept HLA-DR3 Antigen
Concept HLA-B Antigens
Concept HLA-D Antigens
Concept HLA-DQ Antigens
Concept HLA-DR Antigens
Concept HLA-A2 Antigen
Concept HLA-DR4 Antigen
Concept HLA Antigens
Academic Article HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation.
Academic Article A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination.
Academic Article HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange.
Academic Article An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses.
Academic Article Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide.
Academic Article Pillars article: three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993. 364: 33-39.
Academic Article Evaluating the Role of HLA-DM in MHC Class II-Peptide Association Reactions.
Academic Article A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B.
Academic Article The Dendritic Cell Major Histocompatibility Complex II (MHC II) Peptidome Derives from a Variety of Processing Pathways and Includes Peptides with a Broad Spectrum of HLA-DM Sensitivity.
Academic Article Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide-MHC complexes.
Academic Article Structural Insights Into HLA-DM Mediated MHC II Peptide Exchange.
Academic Article Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope.
Academic Article The N-terminal region of photocleavable peptides that bind HLA-DR1 determines the kinetics of fragment release.
Academic Article HLA-DO Modulates the Diversity of the MHC-II Self-peptidome.
Academic Article Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses.
Academic Article Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1).
Academic Article In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls.
Academic Article CDR3a?drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection.
Academic Article A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1.
Academic Article Distinguishing Signal From Noise in Immunopeptidome Studies of Limiting-Abundance Biological Samples: Peptides Presented by I-Ab in C57BL/6 Mouse Thymus.
Concept HLA-DR alpha-Chains
Concept HLA-DRB1 Chains
Academic Article Broadly recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles.
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  • HLA B Antigens