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Pediatric Immunology

Thursday 16 April 2009

Our research effort focuses on the mechanisms that underlie antigen processing- and transport pathways in antigen presenting cells of the immune system. Elucidation of these mechanisms should yield insight in the development of potent immune defense to microorganisms and to the maintenance of immune tolerance. It is our intention to extend basic research findings into improvements in patient care.

We are intrigued by the ability of antigen presenting cells and amongst those especially dendritic cells, to activate quiescent naïve T lymphocytes, which is essential to host defense against infectious disease. At least as important, antigen-presenting cells have a major role in the maintenance of immune tolerance to prevent the development of autoimmune disease. Immature dendritic cells continuously sample their surrounding tissues via pinocytosis and receptor-mediated endocytosis. The encounter of antigens under stimulatory conditions triggers sentinel-type dendritic cells in the mucosae of the lungs and intestinal tract or the skin to migrate to lymph nodes. Stimulation of dendritic cells is most readily attained via ligation of pattern recognition receptors specific for conserved moieties expressed by pathogens, which facilitates the expression of the chemokine receptors (i.e. CCR7) to allow for directed homing to regional lymph nodes. During transit to lymphoid tissues, sampled antigen is processed and displayed as antigen-derived peptide/MHC complexes, essentially providing an antigenic snapshot for inspection by patrolling naïve T lymphocytes in lymph nodes. Other members of the dendritic cell family reside constitutively in lymphoid tissues, and present antigens acquired via afferent lymphatic vessels and the blood, either in free from or transported via migratory cells, for induction of adaptive immune responses to antigens from peripheral sites.

The processes outlined above are generalized and are moreover likely to differ under healthy compared to pathological conditions. Elucidation of the mechanisms that underlie dendritic cell migration, and their processing and presentation of antigenic moieties, should facilitate the development of new therapies to improve the lives of individuals suffering from inherited and acquired immune deviations. We focus our studies on presentation of endosome-derived antigen, which includes the presentation via products of the Class II and Class I MHC locus (in the process of cross-presentation), and lipid presentation in the form of lipid/CD1 complexes.

Our preferred approach lies in novel mouse models, which we combine with experiments using materials from healthy and patient donors. Mouse strains we generated include fluorescent knock-in mice, knock-out mice and transgenic mice. We currently focus our research effort on the mechanisms involved with lipid antigen selection for presentation in thymus and peripheral tissues, for support of invariant NKT cell development and function. We study the tolerance mechanisms in liver and skin using newly developed mouse models, in which T cell responses specific to tissue-expressed antigen are investigated. We moreover study the role of early immune stimulation in lung tissue during infection with respiratory syncytial virus. We develop new tools to extend our work on endosomal processing of antigens for (cross-) presentation via Class I MHC and Class II MHC, with emphasis on receptor-mediated uptake and phagosomal maturation.

Cell culture of T cells and different types of DC, FACS, Elisa, luminex, gel electrophoresis, confocal microscopy, immunohistochemistry, in vivo animal studies

6 or 9 months

Dr. Mark Klein, 088 75 555 55 (pager 4118), mklein01@umcutrecht.nl

More info
Recent publications (a selection):
Kim S, Visser A, Cruijsen C, van der Velden A and Boes M. Recruitment of Rab27a to phagosomes controls microbial antigen cross-presentation by dendritic cells. Infect Immun. 2008 Nov;76(11):5373-80

Sprengers D, Sillé F, Derkow K, Besra G, Janssen H, Schott E, Boes M. Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen. Gastroenterology. 2008 Jun;134(7):2132-43

Scott JE, ElKhal A, Freyschmidt EJ, MacArthur DH, McDonald D, Howell MD, Leung DY, Laouar A, Manjunath N, Bianchi T, Boes M, Oettgen HC, Geha RS. Impaired immune response to vaccinia virus inoculated at the site of cutaneous allergic inflammation. J Allergy Clin Immunol. 2007 Dec;120(6):1382-8

Junt T, Moseman EA, Iannacone M, Massberg S, Lang PA, Boes M, Fink K, Henrickson SE, Shayakhmetov DM, Di Paolo NC, van Rooijen N, Mempel TR, Whelan SP, von Andrian UH. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature. 2007 Nov 1;450(7166):110-4

Majewski M, Bose T, Sillé F, Pollington A, Fiebiger E and Boes M. Protein kinase C delta stimulates antigen presentation by Class II MHC in murine dendritic cells. Int. Immunol. 2007 Jun;19(6):719-32