The interest of the Boes laboratory concentrates on the mechanisms underlying the unique ability of antigen presenting cells (especially dendritic cells) to activate naïve T lymphocytes. Immune defense against infectious disease relies on T cell activation, as does the maintenance of peripheral immune tolerance, in order to prevent the development of autoimmune disease. Our research aims to improve the understanding of the intracellular antigen processing- and transport pathways in antigen presenting cells. To study the intracellular pathways of molecules in antigen presenting cells essential to T cell activation, our preferred approaches range from basic molecular genetics and biochemistry to the generation of novel animal-based models. We employ live cell imaging techniques to track the intracellular antigen processing- and transport pathways in real-time.
The degradation of internalized fragments by dendritic cells triggers the segregation of pathogen-derived protein and lipid moieties in endosomal compartments, followed by possible acquisition by products of the Major Histocompatibility Complex (MHC) locus and CD1, respectively. These pathogen-derived fragments are displayed in complex with MHC or CD1 molecules for recognition by T cells. We generated mice in which all Class II MHC molecules are expressed as fusion proteins of Class II MHC chain and green fluorescent protein (GFP). In such mice, the green fluorescent Class II MHC fusions are expressed from the endogenous locus, therefore under control of the endogenous promotor and enhancer elements. To study the intracellular transport of CD1d molecules and cells that express CD1d, we recently generated CD1d-yellow fluorescent protein (YFP) knock-in mice. Unlike the MHC, CD1 molecules are non-poly¬morphic and present 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. The Class II MHC and CD1d fluorescent mouse models are used to study distinct subtypes of dendritic cells in different anatomical locations. The potent immunogenicity of specialized subsets of dendritic cells residing in the skin indicate strong antigen processing abilities for Class II MHC and CD1d antigen presentation involved in immunity at barrier surfaces. We are interested to study the role of antigen presentation in vivo by dendritic cells from various anatomical locations, in their ability to stimulate T cell activation or induce tolerance.
PUBLICATIONS:
1. M. Boes, C. Esau, M. Fischer, T. Schmidt, M. Carroll, and J. Chen. Enhanced B-1 cell development, but impaired IgG antibody responses in mice deficient in secreted IgM. Journal of Immunology 1998; 160:4776-4787.
2. M. Boes, A. Prodeus, T. Schmidt, M. Carroll, and J. Chen. A critical role of natural Immunoglobulin M in immediate defense against systemic bacterial infection. Journal of Experimental Medicine 1998; 188:2381-2386.
3. L. Gravestein, D. Amsen, M. Boes, C. Revilla Calvo, A. Kruisbeek, and J. Borst. The TNF receptor family member CD27 signals to Jun N-terminal kinase via Traf-2. European Journal of Immunology 1998; 28:2208-2216.
4. M. Boes, T. Schmidt, K. Linkemann, B. Beaudette, A. Marshak-Rothstein, and J. Chen. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci USA 2000; 97:1184-1189.
5. L. Foghsgaard, D. Wissing, D. Mauch, U. Lademann, L. Bastholm, M. Boes, F. Elling, M. Leist, and M. Jäätelä. Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. J Cell Biol. 2001; 153:999-1010.
6. C. Esau, M. Boes, H. Youn, L. Tatterson, J. Liu, and J. Chen. Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. J Exp Med 2001;194(10):1449-59.
7. T. Langford, M. Housley, M. Boes, J. Chen, M. Kagnoff, F. Gillin, and L. Eckmann. Central importance of immunoglobulin A in host defense against Giardia spp. Infect Immun 2002; 70(1):11-8.
8. M. Boes*, E. Pluger*, C. Alfonso, C.J. Schroter, H. Kalbacher, H. Ploegh and C. Driessen. Specific role for cathepsin S in the generation of antigenic peptides in vivo. Eur J Immunol 2002; 32(2):467-76. *contibuted equally.
9. 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. See comment in: Nature. 2002; 418(6901):923-4.
10. M. Boes, N. Bertho, J. Cerny, M. Op den Brouw, T. Kirchhausen and H. Ploegh. T cell induce tubular class II MHC compartments in dendritic cells in a toll-like receptor-dependent manner. Journal of Immunology 2003, 171:4081-8.
11. N. Bertho, J. Cerny, E. Fiebiger, Y. Kim, H. Ploegh and M. Boes. Requirements for T-cell polarized tubulation of Class II+ compartments in dendritic cells. Journal of Immunology 2003; 171: 5689-96.
12. 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.
13. L. Shen, L. J. Sigal, M. Boes and K. L. Rock. Important role of cathepsin S in generating peptides for TAP-independent MHC class I cross presentation in vivo. Immunity 2004; 21(2): 155-65.
14. N. Fehrenbacher, M. Gyrd-Hansen, B. Poulsen, U. Felbor, T. Kallunki, M. Boes, E. Weber, M. Leist and M. Jäättelä. Sensitization to the lysosomal cell death pathway upon immortalization and transformation. Cancer Research 2004; 64 (15):5301-10.
15. A. D. Straw, F. Dzierszinski, M. Boes, D. S. Roos and E. J. Pearce. Functional inactivation of immature dendritic cells by an intracellular parasite. Journal of Immunology, 2004; 173: 2632-40.
16. 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.
17. J.H. Niess, S. Brand, X Gu, L. Landsman, S. Jung, B.A. McCormick, J.M. Vyas, M. Boes, H. L. Ploegh, J. G. Fox, D. R. Littman, and H. C. Reinecker. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005 Jan 14;307(5707):254-8.
18. M. Boes, N. van der Wel, V. Peperzak, Y. Kim, P. Peters and H. Ploegh. In vivo control of endosomal architecture by Class II-associated invariant chain and cathepsin S. 2005 Sept:35(9):2552-62.
19. Y. Kim, J.Y. Pan, G. A. Korbel, V. Peperzak, M. Boes and H. Ploegh. Monovalent ligation of the B cell receptor induces receptor activation but fails to promote antigen presentation. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3327-32.
20. 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.
REVIEWS:
1. M. Boes. Role of natural and immune IgM antibodies in immune responses. Review. Molecular Immunology 2000; 37: 1141-1149.
2. M. Boes, A. Cuvillier and H. Ploegh. Membrane specializations and endosome maturation in dendritic cells and B cells. Invited review, Trends in Cell biology 2004; 14(4): 175-83
3. M. Boes and H. Ploegh. Translating cell biology in vitro to immunity in vivo. Invited review, Nature 2004; 430 (6996): 264-71
4. F. C. Sille, A. Visser and M. Boes. T cell priming by tissue-derived dendritic cells: new insights from recent murine studies. Cell Immunol. 2005 Oct;237(2):77-85.
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