Understanding the Effects of Low Potency TCR Ligands Open Access
Rosenthal, Kristen McCrory (2012)
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
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