Subjects: Biology >> Biophysics >> Immunology submitted time 2016-05-12
Abstract： We previously showed that LIGHT and its receptor herpes virus entry mediator (HVEM) are important for development of optimal CD4(+) Th1 cell immunity and resistance to primary Leishmania major infection in mice. In this study, we further characterized the contributions of this molecule in dendritic cell (DC) maturation, initiation, and maintenance of primary immunity and secondary anti-Leishmania immunity. Flow-cytometric studies showed that CD8 alpha(+) DC subset was mostly affected by HVEM-Ig and lymphotoxin beta receptor-Ig treatment. LIGHT signaling is required at both the priming and the maintenance stages of primary anti-Leishmania immunity but is completely dispensable during secondary immunity in wild type mice. However, LIGHT blockade led to impaired IL-12 and IFN-gamma responses and loss of resistance in healed CD40-deficient mice after L. major challenge. The protective effect of LIGHT was mediated primarily via its interaction with lymphotoxin beta receptor on CD8 alpha(+) DCs. Collectively, our results show that although LIGHT is critical for maintenance of primary Th1 response, it is dispensable during secondary anti-Leishmania immunity in the presence of functional CD40 signaling as seen in wild type mice.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics >> Immunology submitted time 2016-05-12
Xu, Meng
Liu, Mingyue
Du, Xuexiang
Li, Sirui
Li, Hang
Li, Xiaozhu
Li, Ying
Qin, Zhihai
Fu, Yang-Xin
Wang, Shengdian
Xu, Meng
Liu, Mingyue
Du, Xuexiang
Li, Sirui
Wang, Yang
Fu, Yang-Xin
Abstract： Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Immunology submitted time 2016-05-11
Guo, Xiaohuan
Liang, Yong
Zhang, Yuan
Kee, Barbara L.
Fu, Yang-Xin
Guo, Xiaohuan
Liang, Yong
Fu, Yang-Xin
Liang, Yong
Fu, Yang-Xin
Lasorella, Anna
Lasorella, Anna
Abstract： Microbiota-mediated effects on the host immune response facilitate colonization resistance against pathogens. However, it is unclear whether and how the host immune response can regulate the microbiota to mediate colonization resistance. ID2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice in which ID2 is deleted from differentiated ILC3s, we observed that these mutant mice exhibited greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we showed that the ID2-dependent early colonization resistance was mediated by interleukin-22 (IL-22) regulation of the microbiota. In addition to regulating development, ID2 maintained homeostasis of ILC3s and controlled IL-22 production through an aryl hydrocarbon receptor (AhR) and IL-23 receptor pathway. Thus, ILC3s can mediate immune surveillance, which constantly maintains a proper microbiota, to facilitate early colonization resistance through an ID2-dependent regulation of IL-22.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-11
Liu, Xiaojuan
Xu, Hairong
Peng, Hua
Fu, Yang-Xin
Liu, Xiaojuan
Pu, Yang
Cron, Kyle
Deng, Liufu
Fu, Yang-Xin
Xu, Meng Michelle
Pu, Yang
Cron, Kyle
Deng, Liufu
Kline, Justin
Fu, Yang-Xin
Xu, Meng Michelle
Kline, Justin
Frazier, William A.
Abstract： Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c(+) cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Immunology submitted time 2016-05-05
Zhu, Danming
Liu, Longchao
Yang, Dan
Bian, Yingjie
Sun, Zhichen
He, Junming
Zhang, Liguo
Peng, Hua
Fu, Yang-Xin
Liu, Longchao
Bian, Yingjie
Sun, Zhichen
Fu, Sherry
Fu, Yang-Xin
Su, Lishan
Abstract： Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination.
Peer Review Status:Awaiting Review
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