Marianne Boes

Dept of Dermatology
Brigham and Women's Hospital
Harvard Institutes of Medicine, Room 660
77 Avenue Louis Pasteur
Boston MA 02115
phone: 617-525-5569
fax: 617-525-5571
Email: mboes@rics.bwh.harvard.edu
Webpage: The Boes Lab Page
Webpage: The Boes Brigham/Dermatology Lab Page
2 Post-Doctoral Fellows, 2 Graduate Students, 1 Technician

The focus of our research is the unique ability of antigen presenting cells (APCs) and amongst those especially dendritic cells, to activate naïve T lymphocytes, which is essential to immune defense against infectious disease. At least as important, APCs have a major role in maintenance of immune tolerance to prevent the development of autoimmune disease. Dendritic cells contain a highly effective antigen-processing machinery and express high levels of accessory molecules to activate naïve T cells (such as co-stimulatory molecules and adhesion molecules). Our research aims to improve understanding of the intracellular antigen processing- and transport pathways in APCs and should yield insight in the development of potent immune defense to microorganisms and to the maintenance of immune tolerance.

To study the intracellular pathways of molecules essential to T cell activation, our preferred approach is based upon mouse models. These mouse models we then use to extract cells of interest, which we analyze by video microscopy or multicolor flow cytometry. For whole animal studies we analyze the expression of such cells in their native tissue. We generate new mouse models in which membrane proteins of interest are expressed as fluorophore-conjugated fusion proteins in the endogenous locus.

Activation of T lymphocytes requires the presentation of antigen-derived fragments as peptide/MHC complexes on the surface of APCs. We generated mice in which all molecules of the major histocompatibility complex (MHC) Class II are expressed as fusion proteins of Class II MHC and green fluorescent protein (GFP). In such mice, the green fluorescent Class II MHC molecules are expressed into the endogenous locus of Class II MHC molecules, therefore under control of the endogenous promotor and enhancer elements. These mice allow for careful analysis of the intracellular trafficking routes of MHC Class II complexes in APCs.

A second type of T lymphocytes, NKT cells, requires the presentation of antigen-derived fragments as lipid/CD1 complexes to acquire immune functions. To allow for study of the intracellular transport of CD1 molecules and the migration of cells that express CD1 in live mice, we recently generated mice that express fusion proteins of CD1 and yellow fluorescent protein (YFP). Unlike the MHC, CD1 molecules are non-poly­morphic and present antigen-derived lipids rather than peptides to T cells. Whereas CD1 has structural similarity to Class I MHC, its transport routes span the early/recycling to late endosomal/lysosomal compartments, reminiscent of Class II MHC. These two mouse models combined allow for analysis of antigen uptake, its processing and display as complexes that can be seen by appropriately restricted T cells, to further our understanding of APC function under both tolerogenic and infectious conditions.

To allow for visualization of APC migration under steady-state and inflammatory conditions, we are currently generating two new mouse models. Our approach of generating novel mouse models allows for monitoring cells in their native microenvironment under a variety of immune conditions, which we feel will constitute a major step forward in both the cell biology and immunology research.

Papers & Publications:

1. M. Boes, J. Cerny, R. Massol, M. Op den Brouw, T. Kirchhausen, J. Chen and H. Ploegh. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 2002; 418(6901):983-988.
2. D. Palliser, H. Ploegh and M. Boes. Myeloid differentiation factor 88 is required for cross-presentation in vivo. Journal of Immunology 2004; 172: 3415-21.
3. T. A. Rohn, M. Boes, D. Wolkers, S. Spindeldreher, B. Müller, H. Langen, H. Ploegh, A. B. Vogt and H. Kropshofer. Self-peptide CLIP up-regulated on mature dendritic cells antagonizes Th1 polarization. Nature Immunology 2004; 5 (9):909-18.
4. A. Nishibu, B. R. Ward, J. V. Jester, H. L. Ploegh, M. Boes and A. Takashima. Behavioral responses of epidermal langerhans cells in situ to local pathological stimuli. J Invest Dermatol. 2006 Apr;126(4):787-96.
5. M. Majewski, T. Bose, F. Sillé, A. Pollington, E. Fiebiger and M. Boes. Protein kinase C delta stimulates antigen presentation by Class II MHC in murine dendritic cells. Int Immunol. 2007 Jun;19(6):719-32.