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Effects of Differential B cell Receptor Signaling on Memory and Naïve B cell Subset Function and Identification of Novel IgM+ Memory B cell Subsets via Surface Expression of IgD

Gale, Jeremy N. (2017) Effects of Differential B cell Receptor Signaling on Memory and Naïve B cell Subset Function and Identification of Novel IgM+ Memory B cell Subsets via Surface Expression of IgD. Master's Thesis, University of Pittsburgh. (Unpublished)

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The ability to remember antigens and respond quickly to repeat exposure is carried out by long-lived memory cells and is critical for preventing reoccurring infections. Of particular importance to the fields of vaccine development, immunotherapy, and autoimmunity is the study of humoral memory. Our lab has previously identified three subsets within the memory B cell (MBC) compartment delineated by B7-Family members CD80 and PD-L2. These subsets are C80+ PD-L2+ (Double Positive, DP), C80- PD-L2+ (Single Positive, SP) and C80- PD-L2- (Double Negative, DN). B7-Family subsets are predictive of cell fate upon re-exposure to cognate antigen. DP cells quickly become antibody secreting cells (ASCs), while DN MBCs re-enter the germinal center reaction. SP cells possess the capacity to adopt either function. Despite the critical role humoral immunity plays in warding off disease, little is known about how these subsets adopt their respective roles in vivo.
The goal of this project was to further elucidate the differences between CD80/PD-L2 MBC subsets and to understand the significance of these differences in the context of of humoral memory. Given these subsets share the splenic environment and therefore experience similar antigen exposure, we hypothesized that differential regulation of BCR signaling may explain the observed differences in cell differentiation and function. We found that while B7-Family MBC subsets displayed similar proximal BCR signaling, the priming and activation of protein synthesis after BCR cross-linking was significantly different between subsets. Despite few differences in proximal BCR signaling cascades of B7 MBC subsets, we found surface expression of IgD divides the IgM+ MBC compartment into further subsets based on pSyk signaling. IgD+ MBCs have lower pSyk signaling upon re-stimulation with their cognate antigen than those IgM+ cells that lack IgD on their surface. These differences may play a key role in MBC function, and may lead to the discovery of additional functional MBC subsets. Finally, we determined not only that MBCs signal much more strongly throughout the BCR signaling cascade than their naïve counterparts, but these differences are likely caused by a combination of cascade protein levels and decreased phosphatase activity in the MBC compartment.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Gale, Jeremy N.jng28@pitt.edujng28
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairShlomchik, Mark J.mshlomch@pitt.eduMSHLOMCH
Smithgall, Thomastsmithga@pitt.eduTSMITHGA
Kane, Larrylkane@pitt.eduLKANE0000-0001-5198-516X
Milcarek, Christine Amilcarek@pitt.eduMILCAREK
Biswas, Partha S.psb13@pitt.eduPSB13
Date: 23 August 2017
Date Type: Publication
Defense Date: 14 April 2017
Approval Date: 23 August 2017
Submission Date: 1 May 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 39
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Immunology, B cells, B cell Subsets, Memory B cells, Naïve B cells, Signaling, B cell Receptor
Date Deposited: 23 Aug 2017 13:16
Last Modified: 23 Aug 2017 13:16


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