Ira Mellman, Ph.D.

Sterling Professor of Cell Biology & Immunobiology Member, Ludwig Institute for Cancer Research
Phone: (203) 785-4303 Assistant: (203) 785-4302 Fax: (203) 785-4301 e-mail: ira.mellman@yale.edu		Department of Cell Biology Yale University School of Medicine 333 Cedar Street PO Box 208002 New Haven, CT 06520-8002 <Courier Address> 333 Cedar Street, SHM C-439 New Haven, CT 06510-3206

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Our laboratory studies how fundamental mechanisms of membrane traffic control higher order functions such as epithelial cell organization, the immune response, and cancer. Our efforts are currently focused on two distinct but interactive project areas, relying on a wide array of experimental approaches from cell imaging to biochemistry to genetics.

Cell Biology of antigen presentation by dendritic cells. Dendritic cells (DCs) are the most efficient of all antigen presenting cells. They play an essential role in initiating antigen-specific immune responses, and in maintaining tolerance to "self" antigens. Our work has elucidated specializations that account for the DC's efficiency. We have found that DCs regulate their ability to take up protein antigen, convert it into small peptides that can be loaded onto MHC molecules, and translocate the peptide-MHC complexes to the DC surface where they can be recognized by T lymphocytes. This process, known as "maturation", is induced by a number of signals; unraveling the mechanisms and regulation of DC maturation are key to understanding the immune response. Our work is also assisting the development of therapeutic cancer vaccines.

Generation and maintenance of cell polarity. Nearly all our tissues are covered by epithelial cells that regulate our interaction with the outside world. Epithelial cells are polarized, having plasma membranes that are organized into distinct domains: an apical domain facing the exterior world and a basolateral domain facing the interior. We have been unraveling the mechanisms leading to the establishment of membrane polarity: e.g., how cells orient asymmetrically in three dimensions, how they send membrane components to one or the other plasma membrane domain. We have identified signals and adapter complexes responsible for generating polarity in epithelial cells. We have also begun studying how the system breaks down during cancer, and how conserved principles of polarity control DC-T cell interactions during the immune response.

 

 

Selected Publications

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Mellman I. (1996) Endocytosis and molecular sorting. Ann Rev Cell Dev Biol, 12: 575-625.

Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, Mirza A, Inaba K, Steinman RM, Mellman I. (1997) Developmental regulation of MHC class II transport in mouse dendritic cells. Nature, 388: 787-792.

Winckler B, Forscher P, Mellman I. (1999) Polarity in neurons is maintained by a novel diffusion barrier at the axon initial segment. Nature 397: 698-701.

Fölsch H, Ohno H, Bonifacino JS, Mellman I. (1999) A novel clathrin adaptor complex mediates basolateral targeting in polarized epithelial cells. Cell 99: 189-198.

Mellman I and Warren G. (2000) The roads taken: the past and future foundations of membrane traffic. Cell 100: 99-112.

Garrett WS, Chen LM, Kroschewski R, Ebersold M, Turley S, Trombetta S, Galán J, and Mellman I. (2000) Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102: 325-334.

Turley S, Inaba K, Garrett W, Ebersold M, Steinman RM, Mellman I. (2000) Selective transport of MHC class II-peptide complexes and co-stimulatory molecules to the surface of developing dendritic cells. Science 288: 522-527.

Mellman I and Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106: 255-258.

Koivisto U-M, Hubbard AL, Mellman I. (2001) A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Cell 105: 575-585.

Sheff D, Pelletier L, O’Connell CB, Warren G, Mellman I. (2002) Transferrin receptor recycling in the absence of perinuclear recycling endosomes. J Cell Biol 156: 797-804.

Chow A, Toomre D, Garrett W, Mellman I (2002) Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418: 988-994.

Delamarre L, Holcombe H, Giodini A, Mellman I. (2003) Presentation of exogenous antigens on MHC class I and MHC class II molecules is differentially regulated during dendritic cell maturation. J Exp Med 198: 111-122.

Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I. (2003) Regulation of lysosomal function during dendritic cell maturation. Science 299: 1400-1403.

Ang AL, Fölsch H, Mellman I. (2003) The Rab8 and Cdc42 GTPases selectively regulate AP-1B-dependent basolateral transport in polarized MDCK cells. J Cell Biol 163: 339-350.

Folsch H, Pypaert M, Maday S, Pelletier L, Mellman I. (2003) The AP-1A and AP-1B clathrin adaptor complexes define biochemically and functionally distinct membrane domains. J Cell Biol. 163(2):351-62.

Chang HC, Hull M, Mellman I. (2004) The J-domain protein Rme-8 interacts with Hsc70 to control clathrin-dependent endocytosis in Drosophila. J Cell Biol. 164(7):1055-64.

Ang AL, Taguchi T, Francis S, Folsch H, Murrells LJ, Pypaert M, Warren G, Mellman I. (2004) Recycling endosomes can serve as intermediates during transport from the Golgi to the plasma membrane of MDCK cells. J Cell Biol. 167(3): 531-43.

Chow AY, Mellman I. (2005) Old lysosomes, new tricks: MHC II dynamics in DCs. Trends Immunol. 26(2):72-8.

Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES. (2005) Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science. 307(5715):1630-4.

Touret N, Paroutis P, Terebiznik M, Harrison RE, Trombetta S, Pypaert M, Chow A, Jiang A, Shaw J, Yip C, Moore HP, van der Wel N, Houben D, Peters PJ, de Chastellier C, Mellman I, Grinstein S. (2005) Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell. 123(1):157-70.