Biology Reference
In-Depth Information
binding analysis and immunofluorescence, and are able to accumulate adenosine-3-
5-cyclic monophosphate (cAMP) upon receptor engagement
[51]
. These findings
raised the possibility that the
2
AR could be differentially expressed on CD4 T cell
subsets. Similar studies using human Th1 and Th2 cells have either confirmed
[52-54]
or refuted
[55,56]
the findings with the murine effector T cell subsets. Although
we await studies at the gene level, we do know that naïve CD4 T cells, which are
the precursors of both Th1 and Th2 cells, are likely to express the
2
AR, because the
mRNA for the
2
AR has been shown to be expressed in a purified naïve CD4 T cell
population
[57]
, and the earlier radioligand binding studies were likely performed
using the naïve CD4 T cell. Differential expression of the receptor on CD4 T
cell subsets has important implications for how NE might regulate the generation of
a Th1 response, although more work must be done at the gene expression level as the
naïve CD4 T cell differentiates.
Radioligand binding analyses showed that B cells expressed approximately twice
the number of
2
ARs than T cells, although the Kd value of the AR was similar;
that is, the B cell expressed approximately 620 AR binding sites per cell with an
affinity of approximately 0.1 nM
[58-62]
. Adrenergic receptor selective agonists and
antagonists, as well as immunofluorescence, were used to confirm expression of the
2
AR on B cells, while the accumulation of intracellular cAMP was used to measure
signaling of the
2
AR in B cells
[63]
. Similar data have accumulated to show that
such changes occur in both T and B cells following exposure to NE or a
2
AR ago-
nist, confirming expression of a functional receptor on both cell types (reviewed in
Ref.
[15]
).
It will be important to keep in mind that the level of adrenergic receptor expres-
sion varies among the different immune-cell types and is regulated by a variety of
factors, including the activation state of the cell, cytokines, and neurotransmitters
(see
Figure 5.2
and reviewed in Ref.
[15]
). Findings also suggest that the timing of
receptor expression may play an important role in mediating neurotransmitter regula-
tion of immune cells
[64]
. Therefore, when sympathetic innervation of a secondary
Physiological/microenvironment
determinants
Effector function
• Time of neurotransmitter signal
• NE concentration
• Activation state of immune cell
• Hormonal status
• Age
• Stress
• Concentration of immune ligands
Positive regulation
of gene expression
• Receptor expression
• Cytokine production
• Antibody production
• Migration
• Proliferation
NE
NE
Negative regulation
of gene expression
Figure 5.2 Variables that determine the effect of norepinephrine on immune cell
activity and function.
Norepinephrine stimulation of an adrenergic receptor expressed
on an immune cell has the potential to modulate the activity and effector function of
that immune cell. However, the physiological status of the immune cell and/or the
microenvironment in which the immune cell resides determine the level of modulation
mediated by NE, resulting in either positive or negative modulation of gene expression and
subsequent effector function.
