This grant has provided our lab's core support for research on dendritic cells (DCs) and macrophages in mice. In the past funding period, we have expanded a new approach to dissect and direct the function of DCs and macrophages in vivo. The approach is to target different antigens to receptors within monoclonal antibodies (mAbs), either in the steady state or together with stimuli or """"""""adjuvants"""""""". Mab targeting is significant for many reasons. It 1) greatly increases the efficiency of antigen presentation;2) allows one to study receptor and DC subset function in situ without isolating the cells;3) leads to new findings, such as the role of DCs in peripheral tolerance in the steady state;and 4) is moving forward into the clinic to produce new vaccines. As a result of progress since 2005, we are positioned to approach three intertwined aims: 1) to direct Th1 type protective immunity to the parasite Leishmania Major;2) to expand antigen- specific T reg by targeting the self antigen, myelin oligodendroglial glycoprotein, to different receptors in the steady state;3) to directly assess macrophage antigen presentation and consequences in situ, in spleen and lung.
These aims have several innovations: 1) to exploit new anti-DC and anti-macrophage mAbs to overcome the poor ability of defined protein antigens to elicit strong immunity and tolerance in vivo;2) to compare mechanisms for DC and macrophage function side by side in situ, here for expanding antigen specific polarized Th1 immunity and foxp3+ T reg, particularly in the primary T cell repertoire of intact mice;3) to provide homogenous easily shared reagents for wide use and with ability for extension to humans. This research throughout the course of the proposed aims and approaches seeks to overcome several current barriers including: 1) to move away from complex microbial vaccines and learn to induce both immunity and tolerance using defined antigens and adjuvants, with the potential to move this research into humans;2) to be able to compare, side by side DCs and macrophages, focusing on links between innate and adaptive immunity in intact animals;3) to develop strategies that gradually change current emphasis from ovalbumin to clinically relevant antigens, from TCR transgenic T cells to the polyclonal repertoire, and from mice to humans.
The immune system protects us against infections and cancer, and instigates unwanted reactions in allergy and autoimmunity. This grant is developing new approaches to dissect how the immune system works in intact animals and people, and to direct the immune response in a highly specific way.
|Loschko, Jakob; Schreiber, Heidi A; Rieke, Gereon J et al. (2016) Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation. J Exp Med 213:517-34|
|Loschko, Jakob; Rieke, Gereon J; Schreiber, Heidi A et al. (2016) Inducible targeting of cDCs and their subsets in vivo. J Immunol Methods 434:32-8|
|Lee, Jaeyop; Breton, Gaëlle; Oliveira, Thiago Yukio Kikuchi et al. (2015) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. J Exp Med 212:385-99|
|Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana et al. (2015) ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis. PLoS One 10:e0124828|
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|Breton, Gaëlle; Lee, Jaeyop; Liu, Kang et al. (2015) Defining human dendritic cell progenitors by multiparametric flow cytometry. Nat Protoc 10:1407-22|
|Pantel, Austin; Teixeira, Angela; Haddad, Elias et al. (2014) Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol 12:e1001759|
|Mollah, Shamim A; Dobrin, Joseph S; Feder, Rachel E et al. (2014) Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells. J Invest Dermatol 134:1265-1275|
|Anandasabapathy, Niroshana; Feder, Rachel; Mollah, Shamim et al. (2014) Classical Flt3L-dependent dendritic cells control immunity to protein vaccine. J Exp Med 211:1875-91|
|Matos, Ines; Mizenina, Olga; Lubkin, Ashira et al. (2013) Targeting Leishmania major Antigens to Dendritic Cells In Vivo Induces Protective Immunity. PLoS One 8:e67453|
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