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5.9 CD4 T Cells
CD4 T cells are adaptive immune cells that produce cytokines to help activate and
regulate other T cells, macrophages (Th1), or B cells (Th2). NE depletion, either
before or after sensitization in a contact hypersensitivity response, decreased the Th1
cell-mediated response [91] , suggesting that NE might play a role in enhancing Th1
cell development or Th1 cell activity. This possibility was tested when mice became
available that were genetically deficient for the enzyme dopamine beta-hydroxylase,
which is required for the synthesis of NE [92] . These NE-deficient mice produced
less IFN- and were more susceptible to infection with Listeria monocytogenes and
Mycobacterium tuberculosis , suggesting that NE may play a role in enhancing the
level of IFN- produced and the subsequent role that this cytokine plays in protec-
tion through a Th1 cell-mediated immune response.
However, it is still not clear whether NE mediates the effect of IFN- level
enhancement by affecting naïve CD4 T cell activation, naïve CD4 T cell devel-
opment into a Th1 cell, or the level of IFN- produced by the resulting Th1 cells.
Naïve CD4 T cells activated in vitro produced less IL-2 after exposure to NE,
and this effect was prevented when a  2 AR, but not a  1 AR or AR, antagonist was
added [93] . In addition, NE and  2 AR stimulation on a CD4 T cell was reported to
inhibit the activation of NF-B by stabilizing its inhibitor protein IB [94] , which
caused apoptosis and cell death [95,96] . These findings suggest at least two mecha-
nisms by which NE could diminish IL-2 production by a naïve T cell, but fail to
explain the mechanism by which a NE-exposed naïve T cell produces a higher level
of IFN- upon reactivation. Further experiments showed that NE did not affect the
number of Th1 cells that developed into Th1 cells, but did prepare those Th1 cells
that developed to produce more IFN- per cell when reactivated [97] . In this study,
NE did not affect the level of IL-12 secreted by the APC, as has been reported by
others [80,81,98-100] , but this may be due to a difference in experimental design for
APC activation. Thus, the effect exerted by NE to increase the level of IFN- pro-
duced, as suggested by both in vivo and in vitro results, may involve an effect on the
naïve CD4 T cell to prepare the T cell to make more IFN- after it differentiates
into a Th1 cell. It is also possible that NE might affect a CD4 T cell at the effector
stage, as opposed to the naïve T cell stage. In Th1 cells, an increase in intracellular
cAMP inhibited the production of IL-2 [101-103] and IFN- [103] . However, it soon
became clear that the timing of  2 AR stimulation on a Th1 cell in relation to the time
of Th1 cell activation might play an important role in resolving the effect of NE on
Th1 cell activity. For example, exposure of Th1 cells to NE or a  2 AR-selective ago-
nist before their activation decreased both IL-2 and IFN- production [51] . However,
stimulation at either the time of, or after, cell activation appeared to be without effect
or to induce a small increase in IFN- production [104] .
NE may indirectly exert a suppressive effect on Th1 cell development via a direct
effect on either the level of IL-12 produced by dendritic cells or on the ability of
Langerhans cells to migrate to the lymph node [41,105] ; both of these occurrences
would severely hamper naïve T cell activity and differentiation along the Th1 cell
pathway. In vitro exposure of human peripheral blood mononuclear cell (PBMC) to
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