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Negative Regulation of B Cell Responses by Nur77 (Nr4a1)
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Negative Regulation of B Cell Responses by Nur77 (Nr4a1). |
| 개인저자 | Tan, Corey. |
| 단체저자명 | University of California, San Francisco. Biomedical Sciences. |
| 발행사항 | [S.l.]: University of California, San Francisco., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 184 p. |
| 기본자료 저록 | Dissertations Abstracts International 80-12B. Dissertation Abstract International |
| ISBN | 9781392300572 |
| 학위논문주기 | Thesis (Ph.D.)--University of California, San Francisco, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Publisher info.: Dissertation/Thesis. Advisor: Zikherman, Julie. |
| 이용제한사항 | This item is not available from ProQuest Dissertations & Theses.This item must not be sold to any third party vendors. |
| 요약 | B cells are essential players in the humoral immune response, generating both short- and long-lived antibody responses against a wide range of microbes. Rearrangement of the immunoglobulin locus, via V(D)J recombination, leads to vast combinatorial diversity in the B cell receptor (BCR) repertoire. As a result, the precursor frequency of any particular BCR specificity is low, and B cells must clonally expand in order to properly mount an immune response. Despite efficient central tolerance mechanisms, autoreactive B cells persist into the periphery. Thus, B cells must both scale their responses to foreign antigen, and simultaneously prevent inappropriate activation by self-antigens. The molecular mechanisms which restrict B cell responses to self-antigens while facilitating such scaling are incompletely understood.Nr4a1-3 are primary response genes whose expression is induced by mitogenic stimuli in a variety of cell types. The Nr4a genes encode a small family of orphan nuclear hormone receptors that function, in T cells, to mediate antigen-induced cell death as well as other immunoregulatory roles. Although the Nr4a family are among the most highly induced genes in B cells following BCR stimulation, their function in this context is unknown. In this thesis, we examine the expression and functional role of Nr4a1 (Nur77) in B cell responses following both chronic and acute BCR stimulation.We utilize two different models of B cell autoimmunity, the IgHEL/sHEL dTg and VH3H9 models, to study the role of Nur77 in the context of chronic antigen stimulation. In both model systems, endogenous Nur77 expression is elevated in autoreactive B cells. Furthermore, through use of the Nur77-eGFP reporter in which eGFP is placed under the control of the regulatory regions of the Nr4a1 gene, we find that Nur77-eGFP expression correlates with the induction of central and peripheral tolerance mechanisms. Although Nur77 expression was dispensable for receptor editing, central deletion, follicular exclusion, IgM downregulation and anergic BCR signal transduction, we identified a specific role for Nur77 in mediating antigen-induced cell death of self-reactive B cells in the periphery. Nur77-deficient anergic B cells exhibited a survival advantage in vitro and in vivo that was dependent upon antigen and a limiting supply of the B cell survival factor BAFF. Thus, we identified a role for Nur77 in regulating competitive fitness of anergic B cells in the periphery. In the VH3H9 model, loss of Nur77 expression leads to an expansion in the overall size of the B cell compartment, and is sufficient to break tolerance.In the context of acute antigen receptor signaling, we identify a role for Nur77 in restraining the survival and proliferation of B cells which receive BCR stimulation (signal 1) alone, thus enforcing reliance upon costimulatory signals (signal 2). Here, we find that endogenous Nur77 is rapidly and robustly induced following BCR stimulation, and its induction scales with both the amount and affinity of antigen. Through the use of mixed in vitro competitive co-cultures, we find that Nr4a1-/- B cells out compete Nr4a1+/+ B cells in response to BCR stimulation alone. However, this competitive advantage is lost in the presence of costimulatory signals, alone or in conjunction with BCR stimulation. Accordingly, we find increased titers of antigen specific antibody in Nur77-deficient mice immunized with TI-II but not TI-I or T-dependent immunizations. Finally, we identify a competitive advantage of Nr4a1-/- B cells in vivo in response to T-dependent immunizations in contexts where antigen is limiting. Thus, we find that Nur77 acts to restrain B cell responses when B cells receive BCR signaling alone, rendering B cells reliant upon "signal 2", and also acts to restrain B cells in situations where antigen and access to signal 2 is limiting. |
| 일반주제명 | Immunology. |
| 언어 | 영어 |
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