Adaptations to Tonic T cell Receptor Signaling in Naive T Cells Público

Abstract

Naive T cells experience recurrent TCR:self-pMHC signals in the steady state, termed tonic signaling. Such signals are generally inadequate to promote canonical T cell activation. Still, they are sufficient to modulate proximal TCR signaling and induce gene expression changes and epigenetic modifications of naive T cells. Therefore, tonic TCR signals have implications for the responsiveness and differentiation of naive T cells following canonical T cell activation. However, how extensive tonic TCR signaling affects naive CD8+ T cells upon subsequent agonist TCR stimulation remains unresolved. We investigated the heterogeneity and functional implications of tonic TCR signal strength in naive CD8+ T cells by utilizing a transcriptional reporter of Nr4a1 (Nur77-GFP) reflective of TCR signaling. We found that naive CD8+ T cells experience highly variable levels of tonic TCR signaling strength as measured by Nur77-GFP fluorescence intensity. Consistent with Nur77-GFP expression as an indicator of TCR signaling, GFPHI cells exhibited a gene expression profile more indicative of T cell activation than GFPLO cells. However, the cells that experienced the most extensive tonic TCR signaling (GFPHI cells) exhibited diminished IFNy and IL-2 secretion in response to agonist TCR ligand stimulation relative to GFPLO cells. The attenuated responsiveness of GFPHI cells correlated with increased protein levels of Cbl-b, a negative regulator of TCR signaling. Deficiency of Cbl-b partly restored the responsiveness of naive CD8+ GFPHI cells. Our data suggests that extensive tonic TCR signaling induces adaptations of naive CD8+ T cells that attenuate the responsiveness to agonist TCR stimulation. Furthermore, negative regulation induced by strong TCR:self-pMHC signals partly depends on Cbl-b expression. We propose that this de-sensitization of naive T cells may allow the immune system to limit the autoreactive potential of the most self-reactive naive CD8+ T cells.

Table of Contents

Chapter 1: Introduction .......................................................................................................... 1

Markers of tonic signaling........................................................................................................ 3

Role of tonic signaling in CD4+ T cells .................................................................................... 12

Potential mechanisms of negative regulation........................................................................... 16

Role of tonic signaling in CD8+ T cells .................................................................................... 18

Tonic signaling in human T cells ............................................................................................ 19

Tonic signaling strength and adoptive cell therapy................................................................... 20

Outstanding questions in the field........................................................................................... 21

Purpose of the study .............................................................................................................. 21

References ............................................................................................................................ 22

Chapter 2: Cbl-b mitigates the responsiveness of naive CD8+ T cells that experience extensive tonic T cell receptor signaling...................... 40

Abstract .................................................................................................................................... 41

Introduction .............................................................................................................................. 42

Results ...................................................................................................................................... 43

Discussion ................................................................................................................................. 59

Materials and Methods ............................................................................................................... 63 Acknowledgments....................................................................................................................... 72 Figures....................................................................................................................................... 73

Supplemental Information........................................................................................................... 85

References ................................................................................................................................. 98

Chapter 3: Discussion ............................................................................................................... 111

References ............................................................................................................................... 126

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Palabra Clave	Signal transduction T cells TCR
Committee Chair / Thesis Advisor	Byron Au-Yeung, Emory University
Committee Members	Luisa Cervantes-Barragan, Emory University Haydn Kissick, Emory University Arash Grakoui, Emory University Chrystal Paulos, Emory University

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