dc.contributor.advisor | Sharpe, Arlene | |
dc.contributor.author | Finn, Kelsey Kaleen | |
dc.date.accessioned | 2020-10-16T13:35:21Z | |
dash.embargo.terms | 2020-11-01 | |
dc.date.created | 2020-05 | |
dc.date.issued | 2020-04-22 | |
dc.date.submitted | 2020 | |
dc.identifier.citation | Finn, Kelsey Kaleen. 2020. Investigation of Disease-Related T Cell-B Cell Collaboration Events. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. | |
dc.identifier.uri | https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365694 | * |
dc.description.abstract | Orchestrated collaboration between T cells and B cells is crucial for antibody-mediated protection against pathogens but can also underpin the generation of pathogenic B cells that drive chronic inflammatory diseases. The extent of T-B collaboration is tightly regulated to promote affinity maturation and prevent autoreactivity, however the mechanisms by which this regulation occurs remain unclear. T-B collaboration also generates a range of pathogenic B cells that vary in phenotype and function, and a more comprehensive understanding of specific B cell subsets is needed to develop targeted treatments for B cell-mediated diseases.
By studying the humoral response in mice in which the phosphatase PTEN is selectively deleted in the regulatory T cell (Treg) compartment, we have demonstrated that Tregs are required for stringent T follicular helper (Tfh) cell-mediated selection of germinal center (GC) B cells. Immunization of these mice with a model T-dependent antigen revealed a defect in affinity maturation caused by aberrant antigen-driven selection, likely due to uncontrolled and abundant Tfh cell help. Promiscuous selection of GC B cells resulted in enhanced somatic hypermutation and a clonally diverse repertoire, suggesting that specifically inhibiting Tregs could broaden the responding B cell repertoire during vaccination when recognition of subdominant epitopes is critical for protection.
T-B collaboration events outside of the GC, even though they do not result in high affinity antibodies, may nevertheless also contribute to disease. We have identified a potential murine counterpart of human disease-related IgD- CD27- “double negative” (DN) B cells. These IgD-CD148lo murine B cells are expanded in chronic infection and autoimmunity but not after immunization of healthy mice with T-dependent antigens; they are class switched to IgG and exhibit low levels of somatic hypermutation and aberrant selection, suggestive of an extrafollicular origin. These murine B cells closely resemble a previously defined subset of IgD-CD27-CD11c+ DN B cells that are expanded in lupus and also presumed to be of extrafollicular origin. By using TCRb-/-TCRd-/- mice we show that IgD-CD148lo B cells are dependent on T cell help and highlight the utility of manipulating murine counterparts of human immune cells to answer fundamental questions about human disease. | |
dc.description.sponsorship | Medical Sciences | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dash.license | LAA | |
dc.subject | B cells | |
dc.subject | Tfh cells | |
dc.subject | atypical B cells | |
dc.subject | affinity maturation | |
dc.title | Investigation of Disease-Related T Cell-B Cell Collaboration Events | |
dc.type | Thesis or Dissertation | |
dash.depositing.author | Finn, Kelsey Kaleen | |
dash.embargo.until | 2020-11-01 | |
dc.date.available | 2020-10-16T13:35:21Z | |
thesis.degree.date | 2020 | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.level | Doctoral | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Doctor of Philosophy | |
thesis.degree.name | Doctor of Philosophy | |
dc.contributor.committeeMember | Wesemann, Duane | |
dc.contributor.committeeMember | Mayadas, Tanya | |
dc.contributor.committeeMember | Wortis, Henry | |
dc.type.material | text | |
thesis.degree.department | Medical Sciences | |
thesis.degree.department | Medical Sciences | |
dash.identifier.vireo | | |
dash.author.email | kelsey.finn7@gmail.com | |