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Mechanisms of Germinal Center and Non-canonical B cell Responses

Trivedi, Nikita (2020) Mechanisms of Germinal Center and Non-canonical B cell Responses. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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B cell responses to pathogens and vaccines can be mediated by Germinal center (GC) and non-GC processes. Using Ehrlichia muris as a model pathogen for non-canonical B cell responses, we found that antibody forming cells (AFC) and memory B cells (MBC) can be generated in the absence of a GC reaction. In addition, non-lymphoid sites of infection such as the liver can support B cell proliferation, somatic hypermutation (SHM) and MBC generation and localization. Ehrlichia induced B cell responses are marked by diverse surface phenotypes and T-bet expression and a subset of T-bet+ MBC colonize the marginal zone (MZ) compartment of spleen. These data provide insights into non-canonical B cell responses, tissue resident B cell responses and T-bet+ B cell biology.
B cell differentiation into a GC B cell (GCBC) phenotype is marked by distinct B cell receptor (BCR) signaling in comparison to naïve B cells (NBC). This has been attributed to regulatory mechanisms involving protein and lipid phosphatases that function exclusively in GCBC. We extend these findings by uncovering the role of actin as a negative regulator of BCR signaling in NBC and GCBC. In addition, we discover the unique dynamics of BCR endocytosis and antigen (Ag) presentation in GCBC. These data reveal a previously unappreciated role for the lipid phosphatase Phosphatase and tensin homolog (PTEN) in BCR dynamics and Ag presentation. Another lipid phosphatase Src homology 2 domain containing inositol polyphosphate 5-
phosphatase 1 (SHIP-1) is crucial for proliferation and survival of GCBC. Taken together, these data highlight the distinct ways GCBCs are rewired for efficient GC function.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Trivedi, Nikitanit23@pitt.edunit23
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairShlomchik,
Date: 8 January 2020
Date Type: Publication
Defense Date: 6 November 2019
Approval Date: 8 January 2020
Submission Date: 8 January 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 188
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: B cells, germinal center, SHIP-1, actin, Ehrlichia
Date Deposited: 09 Jan 2020 03:17
Last Modified: 09 Jan 2020 03:17


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