Dendritic cells (DC) are the most potent initiators of primary antigen-specific immune responses among antigen presenting cells (APC), including B cells and macrophages. Our ultimate goal is to characterize the molecular mechanisms by which DC express that potency. As a first step, we have identified recently two genes, dectin-1 and dectin-2, by a subtractive cDNA cloning method in which a cDNA library, prepared from a DC line, was subtracted with mRNA isolated from the J774 macrophage line. We have determined that dectin-1 and dectin-2 are both expressed by DC, but not by B cells, macrophages, or other cell lines. With respect to function, we found that both molecules are required for DC-mediated T cell activation. Thus, we have concluded dectin-1 and dectin-2 are members of the costimulatory family. We have also observed that dectin-1 interacts with a polypeptide(s) (dectin-1 ligand) that is (are) expressed on activated T cells.
Modulation of the interactions between costimulatory molecules and their respective ligands is now utilized experimentally to regulate certain immune reactions, including transplantation reactions (induction of anergy or tolerance) and tumor recognition. Thus, biological reagents that interrupt the interaction of costimulatory molecules/ligands are powerful tools for regulation of immune responses. We have proposed that blockage of Dec1/ligand interaction may be applicable for these purposes. In summary, we plan to identify and characterize ligands for dectin-1 and dectin-2. Our studies should provide important insight into molecular mechanisms of DC-mediated T cell activation. Moreover, we believe that the knowledge and reagents developed in these studies will be applicable to the development of new strategies in regulating the to regulate the magnitude, type, and direction of immune responses during tumor immunotherapy and in other clinical settings.
RESEARCH INTERESTS
Immune evasion by melanoma
Role of C-type lectin receptors in innate immunity
Negative regulation of T cell-mediated immunity
RECENT PUBLICATIONS
Bonkobara M. Zukas PK, Shikano S, Nakamura I, Cruz PDJr, Ariizumi K:, "Epidermal Langerhans cell-targeted gene expression by a dectin-2 promoter." J Immunol, 167:6893-6900, 2001
Sato K, Yang X-L, Yudate T, Chung J-S, Wu J, Luby-Phelps K, Kimberly RP, Underhill D, Cruz PD Jr., and Ariizumi K, "Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor chain to induce innate immune responses." J. Biol. Chem., 281:38854-38866, December 2006
Chung J-S, Sato K, Dougherty I, Cruz PD Jr, Ariizumi K., "DC-HIL is a negative regulator of T cell activation." Blood, 109:4320-4327, Spring 2007
Sato K, Shikano S, Xia G, Takao J, Cruz PD Jr, Xie X-S, Ariizumi K, "Selective expression of vacuolar H+-ATPase subunit d2 by particular subsets of dendritc cells among leukocytes" Mol. Immunol., 43:1443-1453, March 2006
Chung J-S, Dougherty I, Cruz PD Jr, Ariizumi K., "Syndecan-4 mediates the co-inhibitory function of DC-HIL on T cell activation." J. Immunol, 179:5778-5784, 2007
SIGNIFICANT PUBLICATIONS
Ariizumi K, Shen G-L, Shikano S, Ritter RIII, Zukas P, Edelbaum D, Morita A, Takashima A., "Cloning of a second dendritic Cell-associated C-type lectin (Dectin-2) and its alternatively spliced isoforms." J Biol Chem, 275:11957-11963, 2000
Shikano S, Bonkobara M, Zukas P, Ariizumi K, "Molecular Cloning of a Dendritic Cell-Associated Transmembrane Protein, DC-HIL, that Promotes RGD-Dependent Adhesion of Endothelial Cells Through Recognition of Heparan Sulfate Proteoglycans." J Biol Chem, 276:8125-8135, 2001
Bonkobara M. Zukas PK, Shikano S, Nakamura I, Cruz PDJr, Ariizumi K:, "Epidermal Langerhans cell-targeted gene expression by a dectin-2 promoter." J Immunol, 167:6893-6900, 2001
Morita A, Ariizumi K, Ritter RIII, Jester JV, Kumamoto T, Johnston SA, Takashima A, "Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter." Gene Therapy, 8:1729-1737, 2001
Chung J-S, Sato K, Dougherty I, Cruz PD Jr, Ariizumi K, "DC-HIL is a negative regulator of T cell activation." Blood, 109:5778-84, 2007
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