IFN-γ Production by Th1 Cells Generated from Naive CD4+ T Cells Exposed to Norepinephrine

Abstract

During activation in vivo, naive CD4+ T cells are exposed to various endogenous ligands, such as cytokines and the neurotransmitter norepinephrine (NE). To determine whether NE affects naive T cell differentiation, we used naive CD4+ T cells sort-purified from either BALB/c or DO11.10 TCR-transgenic mouse spleens and activated these cells with either anti-CD3/anti-CD28 mAbs or APC and OVA323–329 peptide, respectively, under Th1-promoting conditions. RT-PCR and functional assays using selective adrenergic receptor (AR) subtype antagonists showed that naive CD4+ T cells expressed only the β2AR subtype to bind NE and that stimulation of this receptor generated Th1 cells that produced 2- to 4-fold more IFN-γ. This increase was due to more IFN-γ produced per cell upon restimulation instead of more IFN-γ-secreting cells, as determined by IFN-γ-specific immunofluorescence and enzyme-linked immunospot. In contrast, Th1 cell differentiation was unaffected when naive T cells were exposed to NE and activated either in the presence of a neutralizing anti-IL-12 mAb or by APC from IL-12-deficient mice. Moreover, the addition of IL-12 to the IL-12-deficient APC cultures restored the ability of NE to increase Th1 differentiation. Taken together, these results indicate that a possible link may exist between the signaling pathways used by NE and IL-12 to increase naive CD4+ T cell differentiation to a Th1 cell.

Experimental Stroke Induces Massive, Rapid Activation of the Peripheral Immune System

“…Norepinephrine and b2-adrenergic receptor (b2AR) stimulation from infection and injury has been strongly implicated in the regulation of the immune response (reviewed in Kohm and Sanders, 2001), and it is conceivable that brain injury might also transmit sympathetic signals to the spleen. This possible explanation has a number of merits: (1) cytokines such as IL-1b can directly activate sympathetic neurons, which are known to express IL-1R, thus allowing for the possibility that the early induction of IL-1 after stroke might induce efferent sympathetic signals to peripheral lymphoid organs, including spleen; (2) sympathetic stimulation results in the local release of norepinephrine in lymphoid organs including spleen; (3) the b2AR for norepinephrine is selectively expressed by CD4 + T cells and B cells; (4) norepinephrine drives Th1 cell differentiation and secretion of IFN-g through stimulation of b2AR on naïve CD4 + T cells by augmenting the IL-12 signaling pathway (Swanson et al, 2001); (5) norepinephrine increases the number of circulating lymphocytes, and thus might account for the later appearance of T cells in the lymph nodes and blood, which also produced inflammatory cytokines on stimulation through the TCR. Lastly, our novel demonstration of a drastic and rapid release of inflammatory cytokines from activated splenocytes and lymphoid tissue may represent only the initial challenge for the peripheral immune system imperiled by stroke.…”

Grazed grass herbage intake and performance of beef heifers with predetermined phenotypic residual feed intake classification

“…In the present study, lymphocyte functional assays in terms of PHA-and Con A-induced IFN-g production were used to assess immune function. Induction of a proliferative response-induced antigen in vitro has been shown to be representative of cellular immunocompetence (Swanson et al, 2001). This study showed that there were no major differences in immune-specific production of IFN-g in response to stimulation with PHA and Con A between heifers differing in phenotypic RFI.…”

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

“…We are beginning now to understand that catecholamines are an integral part, and potent modulators, of these neuro-endocrine-immune/ inflammatory interactive networks. Through direct communication via sympathetic nerve fibers that innervate lymphoid organs (5), catecholamines can modulate mouse lymphocyte proliferation, differentiation, (6) and cytokine pro-duction of rodent Th cells (7) and human peripheral blood mononuclear cells (PBMCs) (8). These interactions are facilitated by adrenergic receptors expressed on murine lymphocytes (7), rat natural killer (NK) cells (9), rodent macrophages and neutrophils (10,11), and human PBMCs (12).…”