Trivedi, Nikita
(2020)
Mechanisms of Germinal Center and Non-canonical B cell Responses.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38113 |
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