BADERC-Jack L. Strominger

Jack L. Strominger, M.D

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:

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;

Activating and inhibitory immunological synapses in human natural killer cells: how they are formed and how they function, particularly in relation to lipid rafts;

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.

References:

1. 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).

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

7. 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).

8. 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).

9. 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).

10. 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).

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

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

13. 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).

14. 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).

15. 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).

16. 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).

17. 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).

18. 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).






			Jack L. Strominger, M.D 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: 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; Activating and inhibitory immunological synapses in human natural killer cells: how they are formed and how they function, particularly in relation to lipid rafts; 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. References: 1. 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). 2. 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). 3. 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). 4. 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). 5. 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). 6. 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). 7. 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). 8. 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). 9. 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). 10. 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). 11. Boyson, J.E., Rybalov, B., Koopman, L.A., Exley, M., Balk, S.P., Racke, F.K., Schatz, F., Masch, R., Wilson, S.B. and Strominger, J.L. .CD1d and invariant NKT cells at the human maternal-fetal interface. Proc. Natl. Acad. Sci. USA 99 : 13741-13746 (2002). 12. Boyson, J.E., Erskine, R., Whitman, M.C., Chiu, M., Lau, J.M., Koopman, L.A., Valter, M., Angelisova, P. and Strominger, J.L. .Disulfide bond-mediated dimerization of HLA-G on the cell surface. Proc. Natl. Acad. Sci. USA 99:16180-16185 (2002). 13. 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). 14. 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). 15. 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). 16. 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). 17. 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). 18. 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).