To silence autoimmune disease, we seek a means to expand in mice CD25+ CD4+ foxp3+ regulatory T cells(Treg) that are specific for disease producing autoantigens. We will pursue three themes that have begunthrough synergisms with Drs. Nussenzweig and Ravetch in this program: 1) The efficiency of antigenpresentation in vivo can be greatly increased by targeted delivery of antigen within monoclonal antibodies touptake receptors on dendritic cell (DCs). 2) A pivotal feature to the outcome of antigen presentation is thestate of differentiation or maturation of the DC; this can be enhanced or blocked through selective ligation ofactivating and inhibitory FcyR respectively. 3) DCs are specialized antigen presenting cells for CD25+foxp3+ Treg, being able to drive their expansion with maintenance of foxp3 expression and function (5) andto convert CD25- foxp3- T cells into CD25+ foxp3+ T reg (preliminary data). Therefore we will identify DCreceptors, subsets and maturation states that are required to control the development and maintenance ofantigen-specific T reg in the peripheral tissues of mice.
Aim 1 will determine the DC requirements for theexpansion of CD25+ CD4+ foxp3+ antigen-specific Treg in vivo, pursuing initial evidence that the 33D1receptor on CDS- DCs is an effective pathway.
Aim 2 will determine the DC requirements for thedifferentiation of CD25+ CD4+ foxp3+ antigen-specific Treg in vivo from CD25- CD4+ foxpS- progenitors,pursuing initial evidence that the DEC-205 receptor on CD8+ DCs is an effective pathway and that TGFpworks in concert with antigen presenting DCs to generate typical antigen-specific foxp3+ T reg.
Aim 3 willinduce, expand and maintain antigen-specific Tregs from a naive polyclonal T cell repertoire, includingcapacity of DC-targeting antibodies to ligate activating and inhibitory Feyreceptors. By harnessing thebiology of DCs in vivo, particularly by targeting antigens within monoclonal antibodies to uptake receptorsexpressed on DCs, and by controlling the state of differentiation or maturation of DCs, we will be able todefine the priniciples for generating large numbers of disease specific regulatory T cells in intact mice. Thisshould in turn translate into new targeted therapies and products required to control autoimmunity in patientsin a much more disease specific manner than has previously been feasible.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI051573-07
Application #
7645165
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2008-07-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
7
Fiscal Year
2008
Total Cost
$342,514
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Sela, Uri; Park, Chae Gyu; Park, Andrew et al. (2016) Dendritic Cells Induce a Subpopulation of IL-12R?2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses. PLoS One 11:e0146412
Schreiber, Heidi A; Loschko, Jakob; Karssemeijer, Roos A et al. (2013) Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium. J Exp Med 210:2025-39
Bozzacco, Leonia; Yu, Haiqiang (2013) Identification and quantitation of MHC class II-bound peptides from mouse spleen dendritic cells by immunoprecipitation and mass spectrometry analysis. Methods Mol Biol 1061:231-43
Guermonprez, Pierre; Helft, Julie; Claser, Carla et al. (2013) Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. Nat Med 19:730-8
Bozzacco, Leonia; Yu, Haiqiang; Dengjel, Jorn et al. (2012) Strategy for identifying dendritic cell-processed CD4+ T cell epitopes from the HIV gag p24 protein. PLoS One 7:e41897
Meredith, Matthew M; Liu, Kang; Kamphorst, Alice O et al. (2012) Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state. J Exp Med 209:1583-93
Meredith, Matthew M; Liu, Kang; Darrasse-Jeze, Guillaume et al. (2012) Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage. J Exp Med 209:1153-65
Wang, Bei; Zaidi, Neeha; He, Li-Zhen et al. (2012) Targeting of the non-mutated tumor antigen HER2/neu to mature dendritic cells induces an integrated immune response that protects against breast cancer in mice. Breast Cancer Res 14:R39
Bozzacco, Leonia; Yu, Haiqiang; Zebroski, Henry A et al. (2011) Mass spectrometry analysis and quantitation of peptides presented on the MHC II molecules of mouse spleen dendritic cells. J Proteome Res 10:5016-30
Li, Fubin; Ravetch, Jeffrey V (2011) Inhibitory Fc? receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333:1030-4

Showing the most recent 10 out of 40 publications