Regulation of splenic B cell responses by tissue resident macrophages. (360G-Wellcome-106245_Z_14_Z)

£1,413,308

What are you main scientific questions? The spleen is unique from other lymphoid organs in its ability to filter blood antigens. Its large size and highly vascularized nature makes it a central hub for lymphocyte trafficking, cell-cell interactions and information exchange. Dysfunction of the spleen is associated with increased incident of sepsis due to uncontrolled bacterial infections, failure of peripheral tolerance and enhanced proliferation of myeloid cells with pathological potential (4 ). However, despite its importance, the spleen remains largely unexplored and little is known about the nature of cellular movement and interactions within this unique environment. Most of the blood that enters the spleen first reaches the marginal zone (MZ); a narrow compartment that surrounds the B cell follicles and separates them from the open blood circulation of the red-pulp. As such, the MZ represents an important interface for lymphocyte trafficking and antigen capture. Within this regio n, two subsets of resident macrophages have been identified; the marginal-zone macrophages (MZM) and the metallophilic macrophages (MMM) (collectively termed MZ-MQ in this proposal) (fig.1a) (13) . While both MZM and MMM are important for induction of humoral immunity and tolerance (8, 13, 19, 21, 24), the roles each subset plays in these processes and the mechanisms involved are poorly understood. Furthermore it is not known what functional requirements and local cues drive the lineage commitme nt of two distinct macrophage subsets within the same niche and whether or not interactions between them exist. The location of these cells at the entry port to the spleen and in close proximity to B cell follicles suggests that interactions with circulating B cells may affect cell migration and fate. However, this possibility has not been directly tested and a dynamic characterization of the events that take place during B cell entry to the spleen is currently unavailable. We have recently d eveloped a novel procedure that allows us, for the first time, to study cell movement within the spleen of a living mouse in real-time. We propose to use this advanced technology complemented with the development of novel genetic models that target distinct populations of macrophages, to reveal how B cell trafficking and activation is regulated within the spleen. We anticipate that the findings from these studies will have important implication for the rational design of new vaccines, and for th e development of therapeutics for a variety of immunological diseases. Aim-1 Study the role of MZ-MQs in regulating B cell entry to splenic follicles Lymphocyte ability to circulate between lymphoid organs is critical for their function. Over the past 3 decades, the molecular mechanisms of lymphocyte entry into lymph nodes (LNs) have been intensely studied, establishing a well-defined multistep model of entry. In contrast, the manner by which B cells enter the largest lymphoid organ, the sp leen, is only partially understood, largely because visualization of this process has not been achieved. B cells passively enter the MZ with the blood flow and then migrate to the follicles in a CXCR5 and CCR7 dependent manner (9, 10). However, the events that take place within t

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Grant Details

Amount Awarded 1413308
Applicant Surname Arnon
Approval Committee Science Interview Panel
Award Date 2014-12-03T00:00:00+00:00
Financial Year 2014/15
Grant Programme: Title Investigator Award in Science
Internal ID 106245/Z/14/Z
Lead Applicant Dr Tal Arnon
Partnership Value 1413308
Planned Dates: End Date 2022-02-11T00:00:00+00:00
Planned Dates: Start Date 2015-02-12T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East