As one of the most effective weapons in our anti-pathogen artillery, antibodies need to be made and released fast. To accomplish this, antigen-engaged B cells must interact rapidly with antigen-specific helper T cells. At the same time, autoantibody producing B cells must be kept tightiy in check. When B cells encounter antigen in the periphery, whether foreign or self, instead of migrating into B cell areas of secondary lymphoid organs, they move to the outer T cell zones. This relocalization is likely to be critical for favoring encounters with helper T cells and, in the case of autoantigen binding cells, may contribute to their rapid elimination. This study has two long-term goals: to define the mechanism of B cell exclusion from lymphoid follicles following encounter with antigen;and to determine the basis for the rapid elimination of autoantigen binding B cells in the periphery. These goals will be pursued by following three specific aims. First, the molecular cues directing antigen- and autoantigen-binding B cells to the outer T zone will be determined. Recent findings have established that the CXC chemokine, BLC, is important in guiding B cells to follicles, whereas the CC chemokines, ELC and SLC, guide T cells to the T zone. The possibility thai: increased responsiveness to ELC and SLC directs antigen-engaged B cells to the T zone will be explored by genetic approaches.
The second aim will characterize the intracellular signaling pathways downstream of the BCR that promote B cell migration to the outer T zone. A retroviral gene-transduction protocol will oe used to introduce molecules that activate or inhibit specific branches of the BCR signaling pathway, such as dominant negative Ras, MEK or PI3-kinase, to hen egg lysozyme (HEL) specific Ig-transgenic B cells. The genetically modified cells will be returned to mice that contain or lack HEL antigen and the effect of the modification on B cell positioning will be determined. Finally, the third aim is to determine the relationship between B cell positioning and B cell survival. B cells that lack chemokine receptors needed for migration to follicles or T cell areas will be used to test the contribution these compartments make to promcting B cell survival. The involvement of BAFF, a TNF family member, in enhancing the survival of autoreaclive B cells will be explored. As well as improving our understanding of factors regulating the efficiency of B cell antibody production to foreign pathogens, these studies are likely to provide insight into how defects in B rraffirkinp- anH hmnenstasisrnntrihutp tn aiitnimmiinitv or immnnnrlpfiripnrv.
|Lu, Erick; Dang, Eric V; McDonald, Jeffrey G et al. (2017) Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen. Sci Immunol 2:|
|Dang, Eric V; McDonald, Jeffrey G; Russell, David W et al. (2017) Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation. Cell 171:1057-1071.e11|
|Yi, Tangsheng; Li, Jianhua; Chen, Hsin et al. (2015) Splenic Dendritic Cells Survey Red Blood Cells for Missing Self-CD47 to Trigger Adaptive Immune Responses. Immunity 43:764-75|
|Wang, Xiaoming; Sumida, Hayakazu; Cyster, Jason G (2014) GPR18 is required for a normal CD8?? intestinal intraepithelial lymphocyte compartment. J Exp Med 211:2351-9|
|Reboldi, Andrea; Dang, Eric V; McDonald, Jeffrey G et al. (2014) Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345:679-84|
|Cyster, Jason G; Dang, Eric V; Reboldi, Andrea et al. (2014) 25-Hydroxycholesterols in innate and adaptive immunity. Nat Rev Immunol 14:731-43|
|Frey, Sharon E; Winokur, Patricia L; Salata, Robert A et al. (2013) Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario. Vaccine 31:3025-33|
|Yi, Tangsheng; Cyster, Jason G (2013) EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture. Elife 2:e00757|
|Yi, Tangsheng; Wang, Xiaoming; Kelly, Lisa M et al. (2012) Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses. Immunity 37:535-48|
|Kelly, Lisa M; Pereira, João P; Yi, Tangsheng et al. (2011) EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues. J Immunol 187:3026-32|
Showing the most recent 10 out of 40 publications