Understanding the Effects of Low Potency TCR Ligands Open Access

Rosenthal, Kristen McCrory (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/zk51vh77t?locale=en
Published

Abstract


Abstract

Understanding the Effects of Low Potency TCR Ligands

Antigen recognition and subsequent T cell activation is essential for productive cellular
immunity, and depends on a productive encounter between T cell receptors (TCR) and
antigens presented on major histocompatibility complexes (pMHC). Understanding how the
quality and quantity of antigen can affect T cell activation, effector function, and survival is a
necessary part of understanding T cell immunity and function. Moreover, it is hypothesized
that T cells specific for self- or foreign-antigens differ in their affinities, although emerging
evidence indicates that there is a range of affinities in any T cell response, with a larger
subset of low affinity T cells comprising an injurious response to self-peptides. Here we
utilize prototypical self-reactive (myelin) and viral-specific (LCMV) T cells from T cell
receptor (TCR) transgenic mice (2D2 and SMARTA, respectively) to explore how
differences in the quality and quantity of antigen can affect the T cell response. Despite their
dramatically lower 2D affinity for their cognate ligand (>10,000 fold less than SMARTA T
cells), 2D2 T cells respond with complete, albeit delayed, activation as assayed by either
proliferation or cytokine production, and delayed or absent TCR signaling intermediates.
Strikingly, the timing of T cells activation does not change with decreasing doses of antigen
as it does with decreasing affinity, and only the magnitude of the response is affected.
Finally, sustained access to antigen can offset low affinity for a ligand and allow for an
accumulation of signaling intermediates to restore activation. These finding suggests that the
affinity of TCR ligation directs the outcome of response in individual T cell clones, while the
dose of antigen may influence the affinity profile during an immune response by tuning the
scope of the responding T cell populations. Low affinity T cells may be able to escape
tolerance mechanisms and enable autoimmune disease through a smoldering response to the
ever-present self-antigens that propagate disease.


Table of Contents



Table of Contents

About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Degree
Submission
Language
  • English
Research Field
Keyword
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files