Resources Directory
Higgins Professor of Biochemistry

Jack Strominger

Higgins Professor of Biochemistry







Molecular Basis of Immune Recognition

The study of histocompatibility in man and in other vertebrates led to the understanding of the mechanisms of immune recognition and to the discovery of novel molecules and cells involved in these processes, including class I and class II proteins encoded in the major histocompatibility complex of all vertebrates examined and T cell receptors. The normal human response to bacterial and viral infection involves these molecules and results in either the generation of T helper cells and antibodies or of cytotoxic T-lymphocytes. In addition, many important human autoimmune diseases are linked to particular alleles of the class I and class II proteins. Recently, the importance of still another immune recognition system mediated by Natural Killer (NK) cells has become apparent.

My laboratory is focused now on 3 main projects:

  1. The role of MHC proteins and of products of other disease susceptibility genes in human autoimmunity, including multiple sclerosis, diabetes, pemphigus vulgaris and ankylosing spondylitis;
  2. Activating and inhibitory immunological synapses in human natural killer cells: how they are formed and how they function, particularly in relation to lipid rafts;
  3. Uterine decidual lymphocytes and their roles in the immunobiology of pregnancy. This project involves characterizing uterine natural killer (NK) cells, invariant natural killer T (iNKT) cells and T cells and the roles of these lymphocytes and the many unusual proteins they produce in implantation and maintenance of pregnancy.

Selected Publications

Grey, H.M., Kubo, R.T., Colon, S.M., Poulik, M.D., Cresswell, P., Springer, T., Turner, M. and Strominger, J.L.. The small subunit of HL-A antigens is ß2microglobulin. J. Exp. Med. 138: 1608-1612 (1973).

Turner, M.J., Cresswell, P., Parham. P., Strominger, J.L., Mann, D.L., and Sanderson, A.R. Purification and some properties of papain-solubilized histocompatibility antigens from a cultured human lymphoblastoid line, RPMI 4265. J. Biol. Chem. 250: 4512-4519 (1975).

Humphreys, R.E., McCune, J.M., Chess, L., Herrman, H.C., Malenka, D.J., Mann, D.L., Parham, P., Schlossman, S.F. and Strominger, J.L.. Isolation and immunologic characterization of a human, B-lymphocyte-specific, cell surface antigen. J. Exp. Med. 144: 98-112 (1976).

Orr, H.T., Lopez de Castro, J.A., Lancet, D. and Strominger, J.L.. Complete amino acid sequence of a papain-solubilized human histocompatibility antigen, HLA-B7. 2. Sequence determination and search for homologies.Biochem. 18: 5711-5719 (1979).

Bjorkman, P.J., Saper, M.A., Samraoui, B., Bennett, W.S., Strominger, J.L.. and Wiley, D.C. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329: 506-512, 512-518 (1987).

Gorga, J., Horejsi, V., Johnson, D., Raghupathy, R. and Strominger, J.L.. Purification and characterization of class II histocompatibility antigens from a homozygous human B cell line. J. Biol. Chem. 262: 16087-16094, (1987).

Madden, D.R., Gorga, J.C., Strominger, J.L.., and Wiley, D.C. The structure of HLA-B27 reveals nonamer “self-peptides” bound in an extended conformation. Nature 253: 321 (1991).

Latron, F., Pazmany, L., Morrison, J., Moots, R., Saper, M.A., McMichael, A. and J.L. Strominger. A critical role for conserved residues in the cleft of HLA-A2 in presentation of a nonapeptide to T cells. Science 257: 964-967 (1992).

Chicz, M., Urban, R., Gorga, J., Vignali, D., Lane, W.S., and,Strominger, J.L.. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J.Exp. Med. 178: 27-37 (1993).

Brown, J.H., Jardetsky, T.S., Gorga, J.C., Stern, L.J., Urban, R., Strominger, J.L.. and Wiley, D.C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364: 33-39 (1993.)

Stern, L.J., Brown, J.H., Jardetzky, Gorga, J.C., Urban, R., Strominger, J.L.. and Wiley, D.C. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature, 368: 215-221 (1994).

Wucherpfennig, K.W. and Strominger, J.L.. Molecular mimicry in T cell mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell, 80: 695-705 (1995).

Jardetzky, T.S., Brown, J.H., Gorga, J.C., Stern, L.J., Urban, R.B., Strominger, J.L.., and Wiley, D.C. Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II-like conformation for bound peptides. PNAS USA 93: 734-738 (1996).

Santambrogio, L., Sato, A. K., Carven, G. J., Belyanskaya, S.L., Strominger, J.L.. and Stern, L. J. Extracellular antigen processing and presentation by immature dendritic cells. Proc. Natl. Acad. Sci. 96: 15056-15061 (1999).

Strominger, J.L.. MHC proteins and human diseases: a tale of recognition in two immune systems. Japan Prize Commemorative Lecture (1999). Reprinted in Genes and Viruses in Multiple Sclerosis. O.R. Hommes, H. Wekerle, M.Clanet, editors. Elsevier Science: 61-69. (2001)

Falk, K., Rotzschke, O., Santambrogio, L., Dorf, M.E., Brosnan, C. and Strominger, J.L.. Induction and suppression of an autoimmune disease by oligomerized T cell epitopes: enhanced in vivo potency of encephalitogenic peptides. J. Exp. Med. 191: 717-730 (2000).

Falk, K., Rotzschke, O. and Strominger, J.L.. Antigen-specific elimination of T cells induced by oligomerized hemagglutinin (HA) 306-318. Eur. J. Immunol. 30: 3012-3020 (2000).

Wilson, S.B., Kent, S.C., Horton, H.F., Hill, A.A., Bollyky, P.L., Hafler, D.A., Strominger, J.L.. and Bryne, M. Multiple differences in gene expression in regulatory Va 24Ja Q T cells from identical twins discordant for type I diabetes.Proc. Natl. Acad. Sci. USA 97: 7411-7416 (2000).

Shi, F.D., Flodström, M., Balasa, B., Kim, S.H., Gunst, K.V., Strominger, J.L.., Wilson, S.B. and Sarvetnick, N. Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc. Natl. Acad. Sci. USA 98: 6777-6782 (2001).

Santambrogio, L., Belanskaya, S.L., Fischer, F.R., Cipriani, B., Brosnan, C.F., Ricciardi-Castagnoli, P., Stern, L.J.,Strominger, J.L.. and Riese, R. Developmental plasticity of CNS microglia. Proc. Natl. Acad. Sci. USA 98: 6295-6300 (2001).

Re, F. and Strominger, J.L.. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J. Biol. Chem. 276: 37692-37699 (2001).

Naumov, Y.N., Bahjat, K.S., Gausling, R., Abraham, R., Exley, M.A., Balk, S.B., Strominger, J.L.., Clare-Salzer, M. and Wilson, S.B. Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets. Proc. Natl. Acad. Sci. USA 98: 13838-13843 (2001).

Stienekemeier, M., Falk, K., Rotzschke, O., Weishaupt, A., Schneider, C., Toyka, K.V., Gold, R. and Strominger, J.L..Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope.Proc. Natl. Acad. Sci. USA 98: 13872-13877 (2001).

Davis, D.M., Chiu, I., Fassett, M., Cohen, G.B., Mandelboim, O. and Strominger, J.L.. The human natural killer cell immune synapse. Proc. Natl. Acad. Sci. USA 96: 15062-15067 (1999).

Fassett, M.S., Davis, D.M., Valter, M.M., Cohen, G.B. and Strominger, J.L.. Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering. Proc. Natl. Acad. Sci. USA 98: 14547-14552 (2001).

Fridkis-Hareli, M., Santambrogio, L., Stern, J.N., Fugger, L., Brosnan, C., and Strominger, J.L.. Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. J. Clin. Invest. 109: 1635-1643 (2002).

Orange, J, Ramesh, N, Remold-O’Donnell, E., Sasahara, Y., Koopman, L., Brne, M., Bonilla, F., Rosen, F., Geha, R., and Strominger J.L. Wiskott-Aldrich Syndrome protein is required for NK cell cytotoxicity and localizes to NK cell activating immunologic synapses. Proc. Natl. Acad. Sci. USA. 99: 11351-11356 (2002).

Malik, P., Klimovitsky, P., Deng, L., Boyson, J.E., Strominger, J.L.. Uniquely conflrmed peptide-containng B2-microglobulin-free heavy chains of HLA-B2705 molecules on the cell surface. J. Immunol. 169: 4379-4387 (2002).

Boyson, J.E., Rybalov, B., Koopman, L.A., Exley, M., Balk, S.P., Racke, F.K., Schatz, F., Masch, R., Wilson, S.B. andStrominger, J.L.. CD1d and invariant NKT cells at the human maternal-fetal interface. Proc. Natl. Acad. Sci. USA 99: 13741-13746 (2002).

Boyson, J.E., Erskine, R., Whitman, M.C., Chiu, M., Lau, J.M., Koopman, L.A., Valter, M., Angelisova, P. andStrominger, J.L.. Disulfide bond-mediated dimerization of HLA-G on the cell surface. Proc. Natl. Acad. Sci. USA 99:16180-16185 (2002).

Koopman, L.A., Kopcow, H.D., Boyson, J.E., Orange, J.S., Schatz, F., Masch, R., Lockwood, C.J., Schachter, A.D., Park, P. and Strominger, J.L. Human Decidual Natural Killer Cells Are a Unique NK Cell subset with Immunomodulatory Potential. J. Exp. Med. 198(8):1201-12 (2003).

Orange, J.S., Harris, K.E., Andzelm, M.M., Valter, M.M., Geha, R.S., and Strominger, J.L. The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc. Natl. Acad. Sci. USA. 100:14151-14156 (2003).

Deng, L-W., Chiu, I. And Strominger, J.L. MLL 5 protein forms intracuclear foci   and overexpression inhibits cells cycle progression. Proc. Natl. Acad. Sci. USA 101:757-762 (2004).

Santambrogio, L., Wong, S.H., Potolicchio, I., Raposo, G. amd Strominger, J.L. Cleavage of the Ear Domains of the AP-1 Complex by Caspases Controls MHCII Trafficking in Immature Dendritic Cells. I (2004).

Stern, J.N.H., Illes, Z., Reddy, J., Santambrogio, L., Keskin, D.B., Sheu, E., Fridkis-Hareli, M., Nishimura, H., Brosnan, C., Kuchroo, V.K., and Strominger, J.L. Amelioration of PLP 139-151-induced EAE by novel synthetic amino acid copolymers and their mechanisms. Submitted for publication (2004).

Illes, Z., Stern, J.N.H., Reddy, J., Waldner, H., Mycko, M., Brosnan, C.F., Ellmerich, S., Altmann, D.M., Santambrogio, L., Strominger, J.L., and Kuchroo, V.K. Novel synthetic amino acid copolymers suppress MBP 85-99-induced EAE in humanized double-transgenic mice through different effects on T cell responses. Submitted for publication (2004).

Wong, S. H., Santambrogio, L and. & Strominger, J. L. Caspases and Nitric Oxide Broadly Regulate Dendritic Cell Maturation and Surface Expression of Class II MHC Proteins. Proc Natl Acad Sci U S A. 101, 1783-88 (2004).

Stern, J. N.H., Illes, Z., Reddy, J., Keskin, D., Fridkis-Hareli, M., Kuchroo, V.K. and Strominger, J.L. Peptide 15mers of defined sequence that substitute for random animo acid copolymers in amelioration of experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 102:1620-5 (2005).

Krzewski, K., Chen, X., Orange, J.S. and Strominger, J.L. Formation of a WIP, WASp, actin and myosin-II-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. J Cell Biol. 173:121-32 (2006).

Chen, X., Trivedi, P., Ge, B., Krzewski, K. and Strominger, JL Many NK cell activating receptors lead to phosphorylation of ERK2 and JNK1 to trigger MTOC and granule polarization and cytotoxicity PNAS 104(15):6329-34 (2007)

Stern, J.N.H., Keskin, D.B., Zhang, H., Lv, H.-J., Kato, Z. and Strominger, J.L. Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice. PNAS 105:5172–5176 (2008)

Krzewski K and Strominger JL The Killer’s Kiss: The many functions of NK cell Immunological synapses. (2008)Curr Opin Cell Biol. 20,:597-605 (2008)

Strominger JL. Animal antimicrobial peptides: ancient players in innate immunity. J Immunol. 182:6633-4. (2009)