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Interplay of IL-4, IL-21, and ifngamma on memory B cell fate decisions / Naradikian, Martin Souren.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Naradikian, Martin Souren, author.
- Language:
- English
- Subjects (All):
- Immunology.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Local Subjects:
- Immunology.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (133 pages)
- Contained In:
- Dissertation Abstracts International 77-11B(E).
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2016.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- The ability to establish a durable pool of memory B (BMEM) cells is not only a key feature of adaptive immunity but also critical for host survival upon secondary infection. Depending on the nature of the pathogen, preimmune B cells differentiate into various BMEM cells associated with a particular immunoglobulin isotype. Moreover, cytokines dictate this process via the induction of transcription factors resulting in a stable lineage. Recently, the transcription factor, T-BET, has been implicated in reinforcing BMEM cells of the IgG 2c isotype. Further, phenotypically similar cells express the integrin, CD11c, and appear in humoral autoimmunity and aged mice. However, the activation requisites and extrinsic cues driving T-BET and CD11c expression remain poorly defined. T follicular helper (TFH) cells instruct B cells to adopt various BMEM cell fates via the production of cytokines---specifically IL-4, IL-21 and IFNgamma. Here we reveal a novel interplay among these cytokines in determining T-BET+ B cell fate. We find that IL-21 or IFNgamma directly promote T-BET+ B cells in the context of TLR engagement. Further, IL-4 antagonizes IL-21-induced T-BET expression, but augments that of IFNgamma. Finally, IL-21, but not IFNgamma, promotes CD11c expression. Using well-defined infections that drive IL-21 and robust IFNgamma or IL-4 production, we show that these same cytokine interactions function in vivo to determine T-BET and CD11c expression. We elaborate a model in which abundant IFNgamma will drive T-BET+ B cells; however, in the absence of IFNgamma, IL-21 and IL-4 reciprocally regulate both T-BET and CD11c. Importantly, CD11c expression is restricted to BMEM cells, which phenotypically resemble Age-associated B cells (ABCs). In accord with our infection results, we show that T-BET +CD11c+ ABCs are likely a pool BMEM cells. Consistent with this idea, ABCs are somatically mutated, class-switched, and require the ability to present antigen and receive costimulation to form. These findings suggest that T-BET+ B cells seen in health and autoimmunity share the common initiating features of TLR driven activation within this circumscribed cytokine milieu.
- Notes:
- Source: Dissertation Abstracts International, Volume: 77-11(E), Section: B.
- Advisors: Michael P. Cancro; Committee members: David M. Allman; Terri M. Laufer; Michael J. May; Phillip Scott.
- Department: Immunology.
- Ph.D. University of Pennsylvania 2016.
- Local Notes:
- School code: 0175
- ISBN:
- 9781339928999
- Access Restriction:
- Restricted for use by site license.
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