Dendritic cells (DC) exist at the crossroads of innate and adaptive immunity and therefore play a complex and critical role in the host response to infection and in maintenance of self-tolerance. DCs recognize pathogens through a variety of receptors, and this can result in pathogen internalization and rapid production of cytokines that contribute to the inflammatory response. This pathogen recognition also leads to the upregulation of cell surface MHC molecules and costimulatory molecules, which enables DCs to become potent antigen presenting cells presenting pathogen-derived peptides to naive T cells. In this way, DCs are essential for the adaptive immune response, but can also promote autoimmunity if not properly regulated through the inflammatory presentation of self-antigens. DAP12 and FcR3 are two DC-expressed signaling adapters that signal through immunoreceptor tyrosine-based activation motifs (ITAMs). The ITAM-bearing signaling adapters DAP12 and FcR3 regulate DC function in several ways. In vitro, DAP12 and FcR3 inhibit Toll-like receptor (TLR) responses and regulate the anti-inflammatory effects of apoptotic cells on DC function. In vivo, DAP12 and FcR3 regulate DC numbers and contribute to neutrophilia through increased systemic IL-17. Most importantly, DAP12 and FcR3 regulate the maintenance of self-tolerance-DAP12-/-FcR3-/- mice develop lupus-like disease with anti-nuclear antibodies, Ig deposition in the kidney glomeruli and glomerular destruction.
The aims of this proposal seek to define the mechanisms by which DAP12 and FcR3 regulate dendritic cell responses in vivo and in vitro with the goal of identifying how these receptors help protect from the development of lupus-like autoimmunity. Specifically, we will 1) identify the FcR3-associated immunoreceptors required for inhibition of TLR responses in conventional and plasmacytoid dendritic cells;2) test the hypothesis that DAP12 and FcR3 in dendritic cells control neutrophil homeostasis by regulating DC responses to apoptotic cells;and 3) determine if lack of DAP12 and FcR3 specifically in DCs causes the anti-nuclear antibody production and lupus-like disease seen in DAP12-/-FcR3-/- mice. We have shown that DAP12 and FcR3 regulate several aspects of dendritic cell function-TLR signaling, responses to apoptotic cells, and maintenance of self-tolerance-all of which have been associated with the development of lupus-like autoimmunity in mice and humans.
The aims of this proposal seek to define the mechanisms by which DAP12 and FcR3 regulate dendritic cell responses in vivo and in vitro with the goal of identifying how these receptors help protect from the development of lupus-like autoimmunity. These studies will not only help elucidate how dendritic cell function is regulated during immune responses, but also how dendritic cell activation is regulated in the steady state. This work will give insights into how to manipulate the immune system to prevent the development of systemic autoimmunity.
Dendritic cells are important in initiating both inflammatory responses and immune responses. These studies will help elucidate how dendritic cell function is regulated both in the absence and presence of infection. This work will give insights into how to manipulate the immune system to achieve more efficient elimination of pathogens and to prevent the development of systemic autoimmune disease, such as systemic lupus erythematosus.
|Duggan, Jeffrey M; Buechler, Matthew B; Olson, Rebecca M et al. (2017) BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations. Blood 129:1503-1513|
|Hamerman, Jessica A; Pottle, Jessica; Ni, Minjian et al. (2016) Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases. Immunol Rev 269:212-27|
|Buechler, Matthew B; Akilesh, Holly M; Hamerman, Jessica A (2016) Cutting Edge: Direct Sensing of TLR7 Ligands and Type I IFN by the Common Myeloid Progenitor Promotes mTOR/PI3K-Dependent Emergency Myelopoiesis. J Immunol 197:2577-82|
|Buechler, Matthew B; Gessay, Griffin M; Srivastava, Shivani et al. (2015) Hematopoietic and nonhematopoietic cells promote Type I interferon- and TLR7-dependent monocytosis during low-dose LCMV infection. Eur J Immunol 45:3064-72|
|Campanholle, Gabriela; Mittelsteadt, Kristen; Nakagawa, Shunsaku et al. (2013) TLR-2/TLR-4 TREM-1 signaling pathway is dispensable in inflammatory myeloid cells during sterile kidney injury. PLoS One 8:e68640|
|Yee, Nathan K; Hamerman, Jessica A (2013) ?(2) integrins inhibit TLR responses by regulating NF-?B pathway and p38 MAPK activation. Eur J Immunol 43:779-92|
|Buechler, Matthew B; Teal, Thomas H; Elkon, Keith B et al. (2013) Cutting edge: Type I IFN drives emergency myelopoiesis and peripheral myeloid expansion during chronic TLR7 signaling. J Immunol 190:886-91|
|Sun, Xizhang; Wiedeman, Alice; Agrawal, Nalini et al. (2013) Increased ribonuclease expression reduces inflammation and prolongs survival in TLR7 transgenic mice. J Immunol 190:2536-43|
|Giltiay, Natalia V; Chappell, Craig P; Sun, Xizhang et al. (2013) Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med 210:2773-89|
|Ito, Hiroaki; Hamerman, Jessica A (2012) TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells. Eur J Immunol 42:176-85|
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