Dendritic cells (DCs) are specialized antigen presenting cells that can mediate both T cell immunity as well as immune tolerance. The nature of specific maturation signal delivered to DCs is an important determinant of DC function. Fc? receptor (Fc?R) system includes activating as well as inhibitory receptors that are usually co-expressed on the cell surface. The balance between the activating and inhibitory signals determines the outcome of immune complex mediated inflammation and immunity. We have recently shown that selective blockade of the inhibitory Fc?R, Fc?RIIB on DCs leads to DC activation and enhanced generation of T cell immunity. This DC maturation is distinct and characterized by induction of several chemokines and cytokines as well as type I interferon (IFN) response genes. Our preliminary data suggests that Fc?R matured DCs have the ability to activate IL17 producing CD4 as well as CD8 T cells in humans. Our hypothesis is that the balance of Fc?R signaling impacts induction of Th17 cells by DCs.
The aims of this application are I) To compare the properties of human IL17 producing T cells induced by Fc?R activated DCs with those generated by DCs matured with inflammatory cytokines zymosan or peptidoglycan. 2) To evaluate the role of activating Fc?Rs and downstream molecules in DC mediated activation of Th17-1 cells 3) To evaluate the anti-tumor function of the Th17-1 cells induced by DCs loaded with opsonized apoptotic tumor cells. These studies will help us understand the role Fc? receptors on dendritic cell biology and provide novel insights into Fc?R mediated immune regulation in inflammation and disease as well as tumor immunity. .
Dendritic cells (DCs) are specialized antigen presenting cells that mediate activation of T cells. We have previously shown that the function of DCs can be modulated by altering the signaling via their Fc? receptors. In this application we will examine the effect of the modulation of the Fc? receptor balance on the ability of DCs to induce Th17 cells, the pathways involved in the induction of Th17 cells as well as the function of the Th17 cells induced by the DCs.
|Dhodapkar, Madhav V; Dhodapkar, Kavita M (2015) Immune Modulation in Hematologic Malignancies. Semin Oncol 42:617-25|
|Das, Rituparna; Verma, Rakesh; Sznol, Mario et al. (2015) Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol 194:950-9|
|Sehgal, Kartik; Ragheb, Ragy; Fahmy, Tarek M et al. (2014) Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T cell activation via IL-15-dependent DC crosstalk. J Immunol 193:2297-305|
|Sehgal, Kartik; Dhodapkar, Kavita M; Dhodapkar, Madhav V (2014) Targeting human dendritic cells in situ to improve vaccines. Immunol Lett 162:59-67|
|Sehgal, Kartik; Guo, Xiuyang; Koduru, Srinivas et al. (2013) Plasmacytoid dendritic cells, interferon signaling, and Fc?R contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia. Sci Transl Med 5:193ra89|
|Guo, Xiuyang; Dhodapkar, Kavita M (2012) Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum Immunol 73:871-8|