Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Michael P. Cancro

Abstract

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 IgG2c 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 IFNγ. Here we reveal a novel interplay among these cytokines in determining T-BET+ B cell fate. We find that IL-21 or IFNγ 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 IFNγ. Finally, IL-21, but not IFNγ, promotes CD11c expression. Using well-defined infections that drive IL-21 and robust IFNγ 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 IFNγ will drive T-BET+ B cells; however, in the absence of IFNγ, 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.

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