M. Carrie Miceli, Ph.D.

Department Address:
276B Biomedical Sciences Research Building
CAMPUS - 157005
CA

Laboratory Address:
257 Basic Sciences Research Building
Los Angeles, CA 90095

Work Address:
Department of Microbiology, Immunology, and Molecular Genetics
Los Angeles, CA 90095

Affiliations
Affiliations
Co-Director, Center for Duchenne Muscular Dystrophy
Professor, Microbiology, Immunology & Molecular Genetics
Member, Cell & Developmental Biology GPB Home Area, Immunity, Microbes & Molecular Pathogenesis GPB Home Area, JCCC Signal Transduction and Therapeutics Program Area
Research Interests
T cells utilize the T cell receptor (TCR) to specifically recognize antigen in association with self MHC and to signal one of several distinct responses. Under different circumstances, a T cell responds to TCR stimulation by proliferating, dying, differentiating along a particular developmental pathway, producing lymphokines, releasing cytotoxic granules, or by becoming anergic. Recent data suggest that the nature of the ligand stimulating the TCR as well as the signaling molecules included within the TCR "activation complex" can affect the functional consequences of receptor engagement. While considerable progress has been made in understanding TCR signal transduction , it remains unclear how TCR signals are specialized to effect distinct developmental and functional outcomes. We are interested in understanding the molecular basis of TCR signal modulation. We are particularly interested in organizers of the T cell:APC contact and TCR activation complex which are differentially involved in activation of developmentally distinct T cell subsets. Further elucidation of modulators of TCR signals and functions may allow for the intelligent design of vaccines or therapies aimed at immune activation or tolerance induction. Our work directly relates to basic mechanisms of immune regulation, signal transduction, and oncogenesis.
Biography

T cells utilize the T cell receptor (TCR) to specifically recognize antigen in association with self MHC and to signal one of several distinct responses. Under different circumstances, a T cell responds to TCR stimulation by proliferating, differentiating along a particular developmental pathway, producing lymphokines, releasing cytotoxic granules, dying or by becoming anergic. It remains unclear how the functional outcome of TCR engagement is determined . Recent data indicate that the organization of surface receptors, membrane microdomains and signal transducers at the T cell synapse provides a cellular context for TCR/costimulator signal transduction and effector molecule delivery. Lipid raft membrane compartmentalization, intracellular molecular scaffolding, and lectin induced surface glyco-lattice formation represent three potential mechanisms for organizing synaptic microdomains and influencing the outcome of antigenic stimulation. Ongoing studies are aimed at elucidating how alternate microdomain organization can influence contextual TCR signal transduction and how T cell subpopulations differentially capitalize on microdomain organization schemes to modify TCR/costimulator signal transduction and mediate effector function. Further elucidation of modulators of TCR signals and functions may allow for the intelligent design of vaccines or therapies aimed at immune activation or tolerance induction. Our work directly relates to basic mechanisms of immune regulation, signal transduction, tolerence induction, autoimmunity, and oncogenesis.

Publications
Humphries Lisa A, Shaffer Meredith H, Sacirbegovic Faruk, Tomassian Tamar, McMahon Kerrie-Ann, Humbert Patrick O, Silva Oscar, Round June L, Takamiya Kogo, Huganir Richard L, Burkhardt Janis K, Russell Sarah M, Miceli M Carrie Characterization of in vivo Dlg1 deletion on T cell development and function. PloS one. 2012; 7(9): e45276.
Kendall Genevieve C, Mokhonova Ekaterina I, Moran Miriana, Sejbuk Natalia E, Wang Derek W, Silva Oscar, Wang Richard T, Martinez Leonel, Lu Qi L, Damoiseaux Robert, Spencer Melissa J, Nelson Stanley F, Miceli M Carrie Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy. Science translational medicine. 2012; 4(164): 164ra160.
Tomassian Tamar, Humphries Lisa A, Liu Scot D, Silva Oscar, Brooks David G, Miceli M Carrie Caveolin-1 orchestrates TCR synaptic polarity, signal specificity, and function in CD8 T cells. Journal of immunology (Baltimore, Md. : 1950). 2011; 187(6): 2993-3002.
Nelson, Stanley F., Crosbie, Rachelle H., Miceli, M. Carrie, and Spencer, Melissa J. Emerging Genetic Therapies to Treat Duchenne Muscular Dystrophy. , 22 (5): , 2009 Emerging Genetic Therapies to Treat Duchenne Muscular Dystrophy. Current Opinion in Neurology 2009; 22: 532-538.
Liu Scot D, Tomassian Tamar, Bruhn Kevin W, Miller Jeff F, Poirier Françoise, Miceli M Carrie Galectin-1 tunes TCR binding and signal transduction to regulate CD8 burst size. Journal of immunology (Baltimore, Md. : 1950). 2009; 182(9): 5283-95.
Vetrone Sylvia A, Montecino-Rodriguez Encarnacion, Kudryashova Elena, Kramerova Irina, Hoffman Eric P, Liu Scot D, Miceli M Carrie, Spencer Melissa J Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta. The Journal of clinical investigation. 2009; 119(6): 1583-94.
Liu Scot D, Whiting Chan C, Tomassian Tamar, Pang Mabel, Bissel Stephanie J, Baum Linda G, Mossine Valeri V, Poirier Françoise, Huflejt Margaret E, Miceli M Carrie Endogenous galectin-1 enforces class I-restricted TCR functional fate decisions in thymocytes. Blood. 2008; 112(1): 120-30.
Motran Claudia C, Molinder Karen M, Liu Scot D, Poirier Françoise, Miceli M Carrie Galectin-1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function. European journal of immunology. 2008; 38(11): 3015-27.
Round June L, Humphries Lisa A, Tomassian Tamar, Mittelstadt Paul, Zhang Min, Miceli M Carrie Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappaB transcription factors. Nature immunology. 2007; 8(2): 154-61.
Zhang Min, Moran Miriana, Round June, Low Teresa A, Patel Viresh P, Tomassian Tamar, Hernandez Joseph D, Miceli M Carrie CD45 signals outside of lipid rafts to promote ERK activation, synaptic raft clustering, and IL-2 production. Journal of immunology (Baltimore, Md. : 1950). 2005; 174(3): 1479-90.
Round June L, Tomassian Tamar, Zhang Min, Patel Viresh, Schoenberger Stephen P, Miceli M Carrie Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells. The Journal of experimental medicine. 2005; 201(3): 419-30.
Kersh Ellen N, Kaech Susan M, Onami Thandi M, Moran Miriana, Wherry E John, Miceli M Carrie, Ahmed Rafi TCR signal transduction in antigen-specific memory CD8 T cells. Journal of immunology (Baltimore, Md. : 1950). 2003; 170(11): 5455-63.
Huang Tiffany T, Zong Yumei, Dalwadi Harnisha, Chung Chan, Miceli M Carrie, Spicher Karsten, Birnbaumer Lutz, Braun Jonathan, Aranda Richard TCR-mediated hyper-responsiveness of autoimmune Galphai2(-/-) mice is an intrinsic naïve CD4(+) T cell disorder selective for the Galphai2 subunit. International immunology. 2003; 15(11): 1359-67.
Kitchen Scott G, LaForge Stuart, Patel Viresh P, Kitchen Christina M, Miceli M Carrie, Zack Jerome A Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor. Blood. 2002; 99(1): 207-12.
Brewer C Fred, Miceli M Carrie, Baum Linda G Clusters, bundles, arrays and lattices: novel mechanisms for lectin-saccharide-mediated cellular interactions. Current opinion in structural biology. 2002; 12(5): 616-23.
Patel VP, Moran M, Low TA, Miceli MC A molecular framework for two-step T cell signaling: Lck Src homology 3 mutations discriminate distinctly regulated lipid raft reorganization events. Journal of immunology (Baltimore, Md. : 1950) . 2001; 166(2): 754-64.
Miceli MC, Moran M, Chung C, Patel VP, Low T and Zinnanti W Costimulation and counter-stimulation: lipid raft clustering controls TCR signaling and functional outcomes. Seminars in Immunology 2001; 13:2.: 115-128 .
Chung CD, Patel VP, Moran M, Lewis LA, Miceli MC Galectin-1 induces partial TCR zeta-chain phosphorylation and antagonizes processive TCR signal transduction. Journal of immunology (Baltimore, Md. : 1950) . 2000; 165(7): 3722-9.
Vespa GN, Lewis LA, Kozak KR, Moran M, Nguyen JT, Baum LG, Miceli MC Galectin-1 specifically modulates TCR signals to enhance TCR apoptosis but inhibit IL-2 production and proliferation. Journal of immunology (Baltimore, Md. : 1950) . 1999; 162(2): 799-806.
Moran M and Miceli MC Engagement of GPI-linked CD48 Contributes to TCR Signals and Cytoskeletal Reorganization: A Role for Lipid Rafts in T Cell Activation. Immunity 1998; 9: 787-796.
Chung CD, Lewis LA, Miceli MC T cell antigen receptor-induced IL-2 production and apoptosis have different requirements for Lck activities. Journal of immunology (Baltimore, Md. : 1950) . 1997; 159(4): 1758-66.
Lewis LA, Chung CD, Chen J, Parnes JR, Moran M, Patel VP, Miceli MC The Lck SH2 phosphotyrosine binding site is critical for efficient TCR-induced processive tyrosine phosphorylation of the zeta-chain and IL-2 production. Journal of immunology (Baltimore, Md. : 1950) . 1997; 159(5): 2292-300.