Mitchell Kronenberg
e-mail: mitch@liai.org
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Antigen presenting molecules are surface proteins
that present or display ligands for recognition by T lymphocytes. CD1
proteins are antigen presenting molecules that present a distinct category
of antigenic ligands. CD1 reactive T cells may be important for host
defense against pathogens expressing these antigens.
CD1 molecules can present various types of glycolipid antigens, including glycophospatidyl inositols from Mycobacteria and glycosylceramides. A current effort is directed to understanding how CD1 binds to lipids, by testing a series of site directed mutants. Using a series of compounds related to a-galactosyl ceramide, we also are determining the requirements for glycolipid binding to CD1 and for immune stimulation of reactive T cells.
Our previous work has demonstrated that presentation
of glycolipids by human CD1b requires uptake of antigen by the macrophage
mannose receptor (MR), and transport of antigen to endosomes that contain
CD1b. Our current work is designed to more precisely define the endosomal
compartments where CD1 bonds antigen. The MIIC is a specialized mulitlamellar
endosomal compartment where class II molecules that bind to antigenic
peptides. To answer this question, we have generated a variety of CD1
constructs that should direct CD1 traffick to particular endosomal
compartments, including the MIIC.
A second interest is the functioning of the mucosal immune system. We have shown that normal T cells from the spleen can home to the intestine following transfer to immune deficient (SCID) mouse recipients. The engrafted mucosal T cells in the SCID recipients are oligoclonal and homing requires intestinal bacterial flora, suggesting that antigenic stimulation is required. When a purified subpopulation CD4+ T cells is transferred to immune deficient mice but otherwise genetically identical mice, the recipients develop a severe inflammation of the intestine (colitis). Colitis depends upon the secretion of inflammatory cytokines. We are using transgenic mice and gene deficient mice (gene knock outs) to analyze the genetic determinants of this immune mediated disease. We have generated transgenic mice that express the anti-inflammatory cytokine IL-10 under the control of the IL-2 promoter, so IL-10 is expressed by nearly all activated T cells. T cells from these mice can prevent colitis when co-transferred with pathogenic T cells. We are currently analyzing the effect integrin gene deficiencies in mucosal homing and pathogenesis, as well as deficiencies for members of the TNF/TNF receptor gene family.
Cruz, D., Sydora, B.C., Hetzel, K., Yakoub, G., Kronenberg, M. and Cheroutre, H. (1998). An opposite pattern of selection of a single T cell antigen receptor in the thymus and among intraepithelial lymphocytes. Journal of Experimental Medicine (in press).
Ernst , W. A., Maher, J., Cho, S., Niazi, K., Chatterjee, D., Moody, D.B., Besra, G.S., Watanabe, Y., Jensen, P.E., Porcelli, S.A., Kronenberg, M. and Modlin, R.L. (1998). Molecular interaction of CD1b with lipoglycan antigens. Immunity 8:331-340.
Prigozy, T.I., Sieling, P.A., Clemens, D., Behar, S.M., Porcelli, S.A., Brenner, M.B., Stewart, P.L., Modlin, R.L. and Kronenberg, M. (1997). CD1-mediated presentation of a lipoglycan to T cells requires uptake by the mannose receptor and transport to a late endosome. Immunity 6:187-197.
Hagenbaugh, A., Sharma, S., Dubinett, S.M., Wei, S.H.-Y., Aranda, R., Cheroutre, H., Fowell, D., Binder, S., Tsao, B., Locksley, R.M., Moore, K.W. and Kronenberg, M. (1997). Altered immune responses in IL-10 transgenic mice. Journal of Experimental Medicine, 185:2101-2110.
Castaņo, A.R., Tangri, S., Miller,
J.E.W., Holcombe, H.R., Jackson, M.R., Huse, W.D., Kronenberg, M. and
Peterson, P.A. (1995). Peptide binding and presenting properties of
mouse CD1. Science 269:223-226.
Mitchell Kronenberg received his Ph.D. and post doctoral training at the California Institute of Technology. He is the Head of the Division of Developmental Immunology at the La Jolla Institute for Allergy and Immunology.
