Dendritic cells (DCs) are sentinels of the peripheral immune system that continuously survey their surroundings for pathogens, by fluid phase uptake and endocytosis. When pathogen-derived fragments are detected, DCs engulf the foreign material and in the process become activated. Engulfed proteins are processed and displayed as peptide/MHC complexes to Class II MHC-restricted T cells, while lipids are incorporated into CD1/(32m/lipid complexes for presentation to CD1-restricted T cells. Much of what is known about endosomal antigen processing, loading and presentation of Class II MHC molecules was learned through biochemical and cell biological analysis of B cell lines, and to a more limited extent, of cultured DCs. New methodology now makes it possible to visualize the uptake of red fluorescent antigen by live Class II MHC-positive DCs in situ in the epidermis of mice that express green fluorescent protein (GFP)-Class II MHC fusion proteins. Trafficking of antigen-experienced DCs to skin-draining lymph nodes can be tracked in live cells. First, we will study the protein and lipid antigen-presentation pathways in skin-derived DCs and lymph node-resident DCs. We will test our hypothesis that during inflammation, priming of immune responses in the skin requires cell-mediated transport of both protein and lipid antigens by epidermis- resident DCs (Langerhans cells) to skin-draining lymph nodes. Antigen presentation by DCs that reside in the T cell area of lymph nodes is essential for T cell priming. We hypothesize that antigen transfer from LC to a non-migratory lymph node-resident DCs is necessary for successful T cell priming to occur. Accordingly, mutant mice in which LCs express normal antigen endocytosis but defective endosomal processing should have limited phenotype. In contrast, mice expressing non-migratory DCs defective in endosomal processing should exhibit reduced T cell priming capacities. We will study antigen processing and Class II MHC presentation pathways in epidermis-derived Langerhans cells and lymph node-resident DC subtypes. Finally, we have succeeded to generate a new mouse model to study CD1-mediated antigen presentation in vivo. The possible involvement of CD1d to immune responses originating in the skin will be investigated in CD1d- yellow fluorescent protein knock-in mice. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052810-02
Application #
7365095
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
2
Fiscal Year
2008
Total Cost
$208,593
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Vander Lugt, Bryan; Tubo, Noah J; Nizza, Suzanne T et al. (2013) CCR7 plays no appreciable role in trafficking of central memory CD4 T cells to lymph nodes. J Immunol 191:3119-27
Sille, Fenna C M; Martin, Constance; Jayaraman, Pushpa et al. (2011) Requirement for invariant chain in macrophages for Mycobacterium tuberculosis replication and CD1d antigen presentation. Infect Immun 79:3053-63
Sille, Fenna C M; Martin, Constance; Jayaraman, Pushpa et al. (2011) Critical role for invariant chain in CD1d-mediated selection and maturation of V*14-invariant NKT cells. Immunol Lett 139:33-41
Vander Lugt, Bryan; Beck, Zachary T; Fuhlbrigge, Robert C et al. (2011) TGF-? suppresses ?-catenin-dependent tolerogenic activation program in dendritic cells. PLoS One 6:e20099
Koduru, Suresh; Kumar, Lalit; Massaad, Michel J et al. (2010) Cdc42 interacting protein 4 (CIP4) is essential for integrin-dependent T-cell trafficking. Proc Natl Acad Sci U S A 107:16252-6
Bianchi, Teresa; Pincus, Laura B; Wurbel, Marc-André et al. (2009) Maintenance of peripheral tolerance through controlled tissue homing of antigen-specific T cells in K14-mOVA mice. J Immunol 182:4665-74
Boes, Marianne; Stoppelenburg, Arie J; Sille, Fenna C M (2009) Endosomal processing for antigen presentation mediated by CD1 and Class I major histocompatibility complex: roads to display or destruction. Immunology 127:163-70
Sillé, Fenna C M; Boxem, Mike; Sprengers, Dave et al. (2009) Distinct requirements for CD1d intracellular transport for development of V(alpha)14 iNKT cells. J Immunol 183:1780-8
Jin, Haoli; Oyoshi, Michiko K; Le, Yi et al. (2009) IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice. J Clin Invest 119:47-60
Kim, Seong Hyun; Visser, Annelies; Cruijsen, Carin et al. (2008) Recruitment of Rab27a to phagosomes controls microbial antigen cross-presentation by dendritic cells. Infect Immun 76:5373-80

Showing the most recent 10 out of 12 publications