Jack L. Strominger, MD
Higgins Professor of Biochemistry, Harvard University
Department
Area of Research
Structure and Function of Histocompatibility Proteins
Contact Information
Jack L. Strominger, MDDana-Farber Cancer Institute
44 Binney Street
Dana 1410
Boston, MA 02115
Office phone: (617) 632-3083
Fax: (617) 632-2662
E-mail: jlstrom@fas.harvard.edu
Preferred contact method: e-mail
Research
Structure and Function of Histocompatibility Proteins
Our laboratory has been involved in several projects including the study of human immature dendritic cells and central nervous system (CNS) microglia. Human immature dendritic cells express empty major histocompatibility complex (MHC) class II proteins on their cell surface. Thus these cells may be primed for presenting antigens derived
directly from extracellular milieu, without intracellular processing. The discovery that CNS microglia are precursors of both immature dendritic cells and macrophages in the brain parenchyma indicates that these cells represent the primary immune defense system of the CNS. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is responsible for their differentiation in the dendritic cell lineage.
Recent research sheds interesting new light on the regulation of maturation of dendritic cells. Dendritic cells are the primary antigen-presenting lymphocytes in the immune system, and their maturation plays a critical role in responding to foreign antigens derived from invading pathogens. Dendritic cells as they exist in the skin, for example, are immature resting cells. On contact with foreign antigens, however, they rapidly mature and migrate to regional lymph nodes where immune responses are initiated. The major antigen-presenting molecules on dendritic cells (those molecules that directly engage the antigens) are class II MHC proteins. They exist on resting dendritic cells only as "empty" proteins, but on maturation they become filled with peptides and then egress to the cell surface for antigen presentation. To do battle with antigens, they must first get to the cell surface; molecular transport within the cell is thus a key factor in cellular response.
The cells' immature state is characterized by the cleavage of a moderate number of intracellular proteins by caspase-3. These cleavages inhibit many intracellular transport processes and lead to the dormant state. Caspase-3 is inactivated by nitric oxide generated by nitric oxide synthetase, which in turn is induced by lipopolysaccharide and other maturation agents. This allows cell transport to proceed; in vitro cell maturation can be induced by bacterial LPS and other agents.
Recent Awards
- Japan Prize, Science and Technology Foundation of Japan, 1999
- Klemperer Award, New York Academy of Medicine, 1999
- Paul Ehrlich Prize, 1996
- Albert Lasker Basic Medical Research Award, 1995
- National Institute of Medicine, 1975
- National Academy of Sciences, 1970
Biography
Dr. Strominger received his MD in 1948 from Yale Medical School, followed by a research fellowship at Washington University School of Medicine. In 1967 he came to Harvard, and in 1974 joined DFCI, where he was director of basic science until 1977 and chief of the Division of Tumor Virology until 1998. His research focuses on the structure and function of human histocompatibility proteins and their role in disease.
Select Publications
- Stern JN, Illes Z, Reddy J, Keskin DB, Sheu E, Fridkis-Hareli M, Nishimura H, Brosnan CF, Santambrogio L, Kuchroo VK, Strominger JL. Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms. Proc Natl Acad Sci U S A 2004;101:11743-8.
- Santambrogio L, Wong SH, Potolicchio I, Raposo G, Strominger JL. Involvement of caspase cleaved and intact adaptor protein 1 complex in endosomal remodeling in maturing dendritic cells. Nat Immunol 2005;6:1020-8.
- Nieuwenhuis ES, Gillessen S, Scheper RJ, Exley MA, Taniguchi M, Balk SP, Strominger JL, Dranoff GR, Blumberg RS, Wilson SB. CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol 2005;14:250-8.
- Wong SH, Santambrogio L, Strominger JL. Caspases and nitric oxide broadly regulate dendritic cell maturation and surface expression of class II MHC proteins. Proc Natl Acad Sci U S A 2004;101:1783-8.
- Re F, Strominger JL. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J Immunol 2004;173:7548-55.
- Carven GJ, Chitta S, Hilgert I, Rushe MM, Baggio RF, Palmer M, Arenas JE, Strominger JL, Horejsi V, Santambrogio L, Stern LJ. Monoclonal antibodies specific for the empty conformation of HLA-DR1 reveal aspects of the conformational change associated with peptide binding. J Biol Chem 2004;279:16561-70.
- Illes Z, Stern JN, Reddy J, Waldner H, Mycko MP, Brosnan CF, Ellmerich S, Altmann DM, Santambrogio L, Strominger JL, Kuchroo VK. Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells. Proc Natl Acad Sci U S A 2004;101:11749-54.
- Re F, Strominger JL. Separate functional domains of human MD-2 mediate Toll-like receptor 4-binding and lipopolysaccharide responsiveness. J Immunol 2003;171:5272-6.
- Strominger JL, Byrne MC, Wilson SB. Regulation of dendritic cell subsets by NKT cells. C R Biol 2003;326:1045-8.
- Hou R, Goloubeva O, Neuberg DS, Strominger JL, Wilson SB. Interleukin 12- and interleukin 2-induced invariant natural killer T cell cytokine secretion and perforin expression independent of T cell receptor activation. Immunology 2003;110:30-7.
