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ORCID

http://orcid.org/0000-0003-2342-1839

Date of Award

Winter 1-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function

by

Juliet Marie Bartleson

Doctor of Philosophy in Biology and Biomedical Sciences

Immunology

Washington University in St. Louis, 2021

Professor Paul M. Allen, Chair

Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions do not propagate canonical TCR activation pathways, but they do engage proximal TCR signaling molecules and affect basal gene expression patterns. Here, we question whether the strength of tonic signaling directly tunes CD4+ T cell function.

Utilizing a transgenic TCR system, we uncover a role for tonic signaling in predisposing a CD4+ T cell to either T effector (Teff) or T follicular helper (Tfh) lineage commitment early after activation. We then extend these findings to the polyclonal CD4+ T cell repertoire, and through a series of genetic mouse models, we confirm that direct manipulation of tonic signaling strength alters Tfh development. Ultimately, these data establish an inverse relationship between the strength of tonic TCR signaling and Tfh differentiation. Furthermore, we determine tonic signaling strength is also controlling the overall basal metabolic activity of CD4+ T cells, which corresponds with the production of mitochondrial reactive oxygen species. This offers a potential mechanism for how tonic signaling strength influences TCR activation to skew CD4+ T cell fate decisions.

During the course of these studies we generated a novel mouse strain, H2-DMaf/f, to reduce the presentation of self-pMHC, thereby decreasing tonic signaling strength in polyclonal CD4+ T cells. Employing this mouse line, we also interrogated whether there is a specific subset of antigen presenting cells (APCs) responsible for maintaining CD4+ T cell tonic signaling. Our findings indicate a CD11c+ subset of APCs independent of the conventional DC1 lineage is responsible for CD4+ T cell tonic signaling maintenance. Collectively, this work elucidates the critical involvement of tonic signaling in early Teff versus Tfh lineage commitment and enhances our basic understanding of how tonic signaling is being maintained to regulate cellular metabolism during homeostasis.

Language

English (en)

Chair and Committee

Paul M. Allen

Committee Members

Megan Baldridge, Ali Ellebedy, Celeste Morley, Haina Shin,

Available for download on Sunday, September 25, 2022

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