Dr. Maja Maric is an Assistant Professor of Microbiology & Immunology

Summary:

• Ph.D., New York University School of Medicine, 1998
• At Georgetown Since: 2003
• Current lab may consider accepting new Ph.D. students and/or Post Doctoral Fellows. Please contact Dr. Maric for additional information.
• Contact: (202) 687-3749; mam254@georgetown.edu 

Details:

I am interested in the mechanisms of regulation of the immune response as well as host responses to tumors and pathogens.

My research is currently focused on the role of Gamma interferon Inducible Lysosomal Thiol reductase (GILT) in the immune response. All other known mammalian thiol reductases (thioredoxin, ERp57 etc.) have maximum activity at neutral pH while GILT shows peak activity at acidic pH (4-5). Low pH is normally found only in lysosomes intracellularly but some acidification occurs also extracellularly at the sites of inflammation due to injury, infection or autoimmune response.

GILT is synthesized as a proform, matures in endosomal compartment of the cell and is being secreted into the extracellular compartment. We have generated a mouse strain deficient for GILT and we have demonstrated that GILT is an essential component of MHC class II presentation of peptides from proteins rich in disulfide bonds. The presence or absence of GILT can affect immune response to viral, parasite, or tumor antigens, and can affect the development of autoimmune diseases, such as the experimental allergic encephalomyelitis.

Additional Research Information:

My research is currently focused on:

1. Studying effects of GILT on antigen processing. Because of its role in antigen presentation GILT is a potential molecular target for immunotherapy. It is important to examine the effects of absence of GILT on complex processes and diseases, rather than on presentation of model antigens. For example, we want to understand how absence or presence of GILT will affect the repertoire of presented self-peptides. This may have important implications for TCR repertoire selection and development of autoimmune diseases. This project is currently supported by a research grant from American Cancer Society. In collaboration with Dr. Calderone (Georgetown University), we want to study how GILT may affect the course of complex infectious diseases, such as Candidiasis, and in collaboration with Dr. C. Maric (Georgetown University), we are studying a role of GILT in mouse diabetes. 
2. Uncovering other functions of GILT. GILT is philogenetically older than the MHC class II. Therefore, there may be other, nonrelated functions of GILT. Both T and B cells from GILT-deficient mice exhibit altered activation patterns. Uncovering the molecular mechanisms of altered activation will help us understand how a molecule with lysosomal distribution can affect cytoplasmic and/or nuclear processes. To this end we are using a proteomics approach to identify potential substrates of GILT. 
3. Regulation of GILT expression. Unexpectedly, the presence of STAT1, an important messenger for interferon signaling, was not only dispensable, but was in fact detrimental for the constitutive expression of GILT. Interestingly, STAT1 may have opposing effects on constitutive and inducible GILT expression. Therefore another aim of our research is to establish the mechanism of negative regulation of protein expression by STAT-1, using GILT as a model. Continued studies of GILT expression will ultimately: (i) help us modulate the expression of GILT, hence potentially affect the outcomes of various pathological states dependent on antigen processing, (ii) Reveal a novel mode of STAT-1 function and illuminate the poorly understood negative regulatory role of STAT-1 on gene expression. This project is currently supported by a research grant from American Heart Association. 
4. Crystal structure of GILT. In a collaborative effort with Dr. D. Ostrov (University of Florida College of Medicine) we are trying to determine crystal structure of GILT. Family of GILTs appears in distant species, from Paramecium, Branchiostoma, A. thaliana, O. sativum to G. gallus, C. familiaris, M. musculus and H. sapiens and bears no major homology with other known thiol reductases. Therefore, these studies may define a new type of protein fold, as well as help in a search for specific inhibitor of GILT through in silico modeling. Overall, these studies will generate a comprehensive understanding of various aspects of GILT function and expression which will be important for predicting effects of modifying its function, either through human intervention, or potential subversion by microorganisms or ?faulty? genetics. This work will be performed with the essential help of collaborating experts in different fields of biology.

Publications:

M.Maric and Y.Liu. Strong cytotoxic T lymphocyte responses to a MIP1? -expressing tumor: linkage between inflammation and specific immunity.1999. Cancer Research. 59:5549-5553.

P.Cresswell, B.Arunachalam, N.Bangia, T.Dick, G.Diedrich, E.Hughes, M.Maric. 1999.Thiol oxidation and reduction in MHC-restricted antigen processing and presentation. Immunol Res. 19(2-3):191-200.

Review. M.Maric. The Role of MIP1? in anti-tumor immunity and therapy. 2000. Cancer research alert, I:129-131.

U.T.Phan, M.Maric, T.P.Dick, and P.Cresswell. Multiple species express thiol oxidoreductases related to GILT. 2001. Immunogenetics. 53:342-346.

K.Honey, M.Duff, C.Beers, W.H.Brisette, E.A.Elliott, C.Peters, M.Maric, P.Cresswell and A.Rudensky. Cathepsin S regulates the expression of cathepsin L and the turnover of GILT in B lymphocytes. 2001. Journal of Immunology. 276:22573-8.

M. Maric, B. Arunachalam, U.T. Phan, C. Dong, W.S. Garrett, K.S. Cannon, C. Alfonso, L.Karlsson, R.A. Flavell, and P. Cresswell. Defective antigen processing in GILT-free mice. 2001. Science. 294: 1361-1365.

D. Nesic, M. Maric, F. Santori, S.Vukmanovic. Factors influencing the patterns of T cell allorecognition. 2002. Transplantation. 73:797-803.

Phan, U.T., Maric, M. Cresswell, P. Disulfide reduction in major histocompatibility complex class II-restricted antigen processing by interferon-gamma-inducible lysosomal thiol reductase. Methods Enzymol. 2002,43-8.

M.A.Haque, S.K. Jackson, J.W. Hawes, U.T. Phan, M. Maric, P. Cresswell, J.S. Blum. Absence of GILT in melanomas disrupts T cell recognition of an immunodominant epitope. 2002. J.Exp.Med. 20;195(10):1267-77.

G.Sinnathamby, M.Maric, P. Cresswell, L.C. Eisenlohr. Differential requirements for endosomal reduction in the presentation of two I-Ed restricted epitopes from influenza hemagglutinin. 2004. Journal of Immunology. 172: 6607 - 6614.

Barjaktarevic´ , I., A. Vollmer, A. Rahman, B. Bogunovic´ , S. Radoja, S. Vukmanovic´ , & M. Maric´ . Inhibitory role of gamma interferon-inducible lysosomal thiol reductase (GILT) in T cell activation. 2006. Journal Of Immunology. 177:4369-4375.