T cell recognition of weak ligands activates negative regulatory pathways Pubblico
Edwards, Lindsay J (2011)
Abstract
The outcomes of T cell interaction with antigen are determined
by a complex integration
of positive and negative signaling events downstream of the T cell
receptor. The
introduction of amino acid substitutions into the antigenic peptide
provide an opportunity
to alter T cell activation by modulating the affinity of the T cell
receptor for the peptide:
MHC complex or by altering the stability of the peptide: MHC
interaction itself. Both of
these strategies can generate ligands that drive atypical T cell
activation by stimulating
negative regulatory pathways, which we demonstrate with an
antagonist in a model
antigen system, an MHC variant peptide in a type 1 diabetes system
and a myelin antigen
in an in vivo model of multiple sclerosis. The effects of these
weak ligands are evident as
both antagonism and MHC variant peptide treatment induce a stable
hypoproliferative
phenotype. These two stimulations differ somewhat in their outcomes
as antagonism
drives a response in which IL-2 is highly produced, whereas the MHC
variant peptide
stimulates a classic anergic phenotype is which the T cells fail to
produce IL-2 in
response to an agonist ligand. Both antagonism and this form of
anergy have been shown
to rely on the tyrosine phosphatase SHP-1. As self antigens are
generally thought to be
relatively weak ligands, we sought to determine the effects of
SHP-1 deficiency on the
autoimmune disease experimental autoimmune encephalomyelitis (EAE).
Despite data
that SHP-1 is a negative regulator of T cell activation, we found
that deletion in T cells
decreased both the incidence and severity of EAE. This effect
appears to depend upon
the presence of CD4+Foxp3+ T cells, as depletion of these cells
resulted in disease
severity similar to that of control groups. These results suggest
that the function of SHP-
1 in T cell biology is more complex than simple negative regulation
of activation, and
that the consequences of SHP-1 activation may vary between subsets
of T cells.
Collectively, our data demonstrate that T cell stimulation by both
weak ligands and self
antigens can drive the activation of negative regulatory pathways,
thus leading to a
continuum of functional responses.
Table of Contents
Table of Contents
Chapter 1
Introduction........... 1
Figure 1.1 Two dimensional analysis of T cell: pMHC interactions....... 21
Figure 1.2 Spare receptor behavior of TCR....... 22
Chapter 2
A unique unresponsive CD4+ T cell phenotype post TCR antagonism........... 23
Figure 2.1 72I acts as a TCR antagonist........ 35
Figure 2.2 Antagonism causes blunted proliferation but normal IFN-g production in response to wild type peptide........ 36
Figure 2.3 Antagonized cells exhibit altered IL-2 production........ 37
Figure 2.4 Antagonism does not induce apoptosis or alter IL-2R expression........ 38
Figure 2.5 Exogenous IL-2 restores proliferation of pre-pulsed but not antagonized cells........ 39
Chapter 3
Induction of unresponsiveness in diabetogenic T cells by MHC variant peptides............ 40
Figure 3.1 Alignment of parent and variant peptide sequences........ 55
Figure 3.2 BDC2.5 T cells do not proliferate in response to variant peptide........ 56
Figure 3.3 Variant stimulation induces no detectable Erk1/2 phosphorylation........ 57
Figure 3.4 Variant stimulated cells exhibit increased total tyrosine phosphatase and specific SHP-1 phosphatase activity........ 58
Figure 3.5 Variant peptide treatment induces anergy........ 59
Figure 3.6 Addition of exogenous IL-2 does not rescue proliferation of anergized T cells........ 60
Figure 3.7 MHC variant peptide anergized cells are resistant to signaling through the IL-2 receptor........ 61
Chapter 4
T cell specific deletion of the phosphatase SHP-1 decreases incidence and severity of experimental autoimmune encephalomyelitis........... 62
Figure 4.1 SHP-1 expression and activity are decreased in conditional deletion animals........ 81
Figure 4.2 Mice with SHP-1 deficient T cells exhibit decreased incidence and severity of EAE........ 82
Table 4.1 Summary of EAE data for FL-SHP1 Mx1-Cre....... 83
Figure 4.3 Macrophages and microglia in the CNS at peak of EAE are not altered by T cell-specific SHP-1 deletion........ 84
Figure 4.4 Lymphocytic infiltrates in the CNS at peak of disease are not altered by T cell-specific SHP-1 deletion........ 85
Figure 4.5 CNS infiltrating Foxp3+ and tetramer positive T cells are not altered by T cell-specific SHP-1 deletion........ 86
Figure 4.6 Depletion of CD25+ cells effectively depletes the Foxp3+ population........ 87
Figure 4.7 Depletion of CD25+ cells exacerbates EAE in animals with SHP-1 deficient T cells........ 88
Figure 4.8 The frequency of CD4+Foxp3+ cell in mice receiving CD25 depleted T cells increases under control but not SHP-1 deficient conditions........ 89
Chapter 5
Discussion........... 90
Figure 5.1 The stimulatory capacity of an antigenic peptide is determined by its interactions with both the MHC as well as the TCR........ 103
Figure 5.2 Model of T cell signaling events following stimulation with and strong or weak ligand....... 104
References........... 105
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