A critical component of the acute inflammatory response is the rapid mobilization of blood- borne lymphocytes into secondary lymphoid organs. These organs are the staging ground for lymphocyte encounters with antigens and foreign pathogens during the initiation of protective immunity. Significant progress has been achieved in defining the adhesion events that guide homeostatic steady-state trafficking of lymphocytes across vascular checkpoints in lymphoid organs. By contrast, the molecular basis of inducible trafficking of naive and central memory cells to lymphoid organs during inflammation is poorly understood. Extensive preliminary data lead us to hypothesize that the proinflammatory cytokine, interleukin-6 (IL-6), is a driving force in regulating lymphocyte migration into lymphoid organs during acute inflammation.
The first aim will identify the cellular source of IL-6 that regulates the capture efficiency of vascular gateways in a model of systemic febrile inflammation. Reciprocal bone marrow chimeras with wild-type and IL-6-deficient mice will segregate whether IL-6 production by radiation-resistant stromal cells or radiation-sensitive hematopoietic cells is required for enhanced lymphocyte trafficking across vessel walls during febrile stress. Homing assays and intravital microscopy will further validate that a defined cellular source of IL-6 promotes lymphocyte influx into lymphoid organs.
Aim 2 will focus on determining if IL-6 is also responsible for mobilizing the recruitment of naive cells to local inflamed lymph nodes during an adaptive immune response. These studies are based on our surprising discovery that IL-6 produced by mature dendritic cells modifies the adhesive properties of vascular entryways.
The final aim will use genetic approaches to dissect the IL-6 downstream signal transduction pathways that regulate lymphocyte trafficking during local and systemic adaptive immune responses. The studies will use mutant mouse lines that have specific defects in IL-6 signaling pathways in order to map the molecular mechanisms required for accelerated lymphocyte trafficking during acute inflammation. Understanding the cytokine requirements for lymphocyte recruitment during acute inflammation may lead to novel intervention strategies in chronic inflammatory disorders as well as provide insights into vaccine approaches based on the ability of IL-6 to heighten adaptive immunity.
This proposal addresses fundamental questions in immunology regarding the mechanisms governing trafficking of lymphocytes to lymphoid organs during acute inflammation, a function that is crucial for host protection against pathogens. The molecular mechanisms that mediate basal trafficking of lymphocytes to lymphoid organs are well defined, however, little is known about the means of augmenting lymphocyte trafficking during acute inflammation. The proposed studies are expected to provide important insights into the unique role of cytokines in dynamically regulating leukocyte trafficking at key vascular checkpoints. These studies further have the potential to lead to novel therapeutic targets for the promotion of immune surveillance as well as for the treatment of chronic inflammation.
|Ito, Fumito; Evans, Sharon S (2016) Pre-resectional Radiofrequency Ablation as a Neoadjuvant in situ Tumor Vaccine. J Vaccines Vaccin 7:|
|Mikucki, Maryann E; Skitzki, Joseph J; Frelinger, John G et al. (2016) Unlocking tumor vascular barriers with CXCR3: Implications for cancer immunotherapy. Oncoimmunology 5:e1116675|
|Fisher, Daniel T; Muhitch, Jason B; Kim, Minhyung et al. (2016) Intraoperative intravital microscopy permits the study of human tumour vessels. Nat Commun 7:10684|
|Ku, Amy W; Muhitch, Jason B; Powers, Colin A et al. (2016) Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes. Elife 5:|
|Evans, Sharon S; Repasky, Elizabeth A; Fisher, Daniel T (2015) Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 15:335-49|
|Ito, Fumito; Ku, Amy W; Bucsek, Mark J et al. (2015) Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer. PLoS One 10:e0143370|
|Mikucki, M E; Fisher, D T; Matsuzaki, J et al. (2015) Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun 6:7458|
|Pitzonka, Laura; Ullas, Sumana; Chinnam, Meenalakshmi et al. (2014) The Thoc1 encoded ribonucleoprotein is required for myeloid progenitor cell homeostasis in the adult mouse. PLoS One 9:e97628|
|Fisher, Daniel T; Appenheimer, Michelle M; Evans, Sharon S (2014) The two faces of IL-6 in the tumor microenvironment. Semin Immunol 26:38-47|
|Repasky, Elizabeth A; Evans, Sharon S; Dewhirst, Mark W (2013) Temperature matters! And why it should matter to tumor immunologists. Cancer Immunol Res 1:210-6|
Showing the most recent 10 out of 15 publications