Initial Evidence That Norepinephrine Plays a Role in Regulating Adaptive Immune Cell Activity

After infection, immune cells of the adaptive immune system, CD4+ and CD8+ T cells and B cells, protect the host by specifically destroying the infectious pathogen and by providing pathogen-specific long-term protection. Thus, the adaptive immune system acts in an antigen-specific manner, generates long-term protection, and is divided into two major branches: the cell-mediated and humoral. Due to the ability of CD4+ T cells to activate or "help" B cells to make antibody, these cells were called T helper (Th) cells. The ability of CD4+ T cells to promote either a cell-mediated or a humoral response was first understood when Mosmann et al. (1986), and later Romagnani et al. (1991), showed that clones of CD4+ T cells from mice and humans, respectively, could be divided into two distinct effector subsets, Th1 and Th2 cells, based on the cytokines that they produced.We now know that the two effector cell subsets are derived from a common precursor cell called the naive CD4+ T cell [reviewed in (Swain et al., 1996)]. The B cell is responsible for generating the humoral antibody response and is provided help to do so by the CD4+ effector cells. The following sections in this chapter will focus on the evidence that NE plays a role in regulating CD4+ T-cell and B-cell activity.

Pharmacological evidence for involvement of the sympathetic nervous system in regulating the level of an immune response has been obtained using the chemical neurotoxin 6-hydroxydopamine (6-OHDA), a drug that depletes NE from peripheral sympathetic nerve terminals by first displacing NE from the terminal and then reversibly destroying the terminal of adult mice for 4-8 weeks. When the SNS of mice was deleted using 6-

OHDA, immune responses were found to be either enhanced, suppressed, or unaltered [reviewed in (Kohm and Sanders, 2001)], suggesting that NE either suppressed, enhanced, or had no effect, respectively, on an immune response when it was released within the vicinity of immune cells responding to antigen. However, differences in the dose and/or time of 6-OHDA administration and the type of immune response being measured make it difficult to conclude whether these disparate findings reflect different aspects of a related phenomenon.

With these caveats in mind, studies that used NE-depleted mice showed that Th1 cell-mediated immune responses were suppressed. For example, when mice were exposed to 6-OHDA before sensitization with the hapten Trinitrochlorobenzene (TNCB), the resulting Th1 cell-mediated contact hypersensitivity response was decreased in comparison with NE-intact controls (Madden et al., 1989).This finding suggested that NE was required for the generation of a Th1 cell-mediated immune response and may have affected the precursor cell from which the Th1 cell develops. Also, if mice were treated with 6-OHDA at least 3-5 days after sensitization with TNCB, a time when activated nave CD4 + T cells were committed to differentiate into Th1 cells, the resulting contact hypersensitivity response was also decreased (Madden et al., 1989). Thus, this study indicated that chemical sympathectomy was suppressive both during naive T-cell priming and at a time when the cells were committed to the Th1-cell phenotype, suggesting that NE was needed at both the nave and effector stages for an optimal Th1 cell-mediated response to develop. However, one limitation to this experimental design is that the cells may have been exposed to the large bolus of NE released after 6-OHDA treatment, so that it is unclear whether this NE signal, or the lack of NE, was responsible for the effects measured.

To begin to address this possibility, mice that are genetically deficient for the enzyme dopamine ß-hydroxylase, which is required to synthesize NE from dopamine, were used to determine if NE regulates the magnitude of a Th1 cell-driven response (Alaniz et al., 1999). These NE-deficient mice showed a significant decrease in the level of IFN-y produced by CD4+ T cells and in immunological protection when exposed to the Th1-promoting pathogens Listeria monocytogenes or Mycobacterium tuberculosis. These data show that the absence of NE results in a diminished Th1 cell-driven response in vivo, suggesting that NE plays a role in upregulating the magnitude of a Th1 cell-mediated immune response. However, one caution is that due to the deficiency of dopamine ß-hydroxylase, these mice expressed an increase in the level of dopamine (Alaniz et al., 1999). Because dopamine has been shown to decrease CD4+ T-cell function (Kauassi et al., 1987), the decrease in the NE-deficient mice may not be due to the absence of NE but rather due to the exposure of the T cells to concentrations of dopamine that are higher than in wild-type mice. Nonetheless, taken together, these studies are the first to indicate that NE may exert an enhancing effect on either early nave CD4 + T-cell development into a Th1 cell, the commitment to becoming a Th1 cell, and/or the amount of IFN-y secreted by the Th1 cell.

The role that NE plays in a Th2 cell-driven response is less clear, and the role it plays in a Th1 cell-mediated response has been challenged. When two strains of mice, C57Bl/6J (Th1 cell-slanted strain) and Balb/c (Th2 cell-slanted strain), were depleted of NE and immunized 2 days later with the T cell-dependent antigen KLH, splenic cells from both strains of mice produced significantly higher levels of IL-2 and IL-4 after reactivation in vitro when compared with cells isolated from NE-intact controls (Kruszewska et al., 1995). Although IFN-y levels were not determined, the increase in serum IgG2a in these mice suggested that this cytokine was also increased when NE was depleted. These results refute the results described above indicating that NE may exert an enhancing effect on Th1 cell development and/or IFN-y production. Thus, it remains unclear whether or not NE is needed to obtain an optimal Th1 cell-driven response in vivo.

The role played by NE in regulating the magnitude of an antibody response has also been studied in 6-OHDA-induced NE-depleted mice. Unfortunately, however, in vivo results show either a decrease (Kasahara et al., 1977b; Hall et al., 1982; Livnat et al., 1985; Cross et al., 1986; Fuchs et al., 1988; Madden et al., 1989; Ackerman et al., 1991b) or increase (Besedovsky et al., 1979; Miles et al., 1981; Chelmicka-Schorr et al., 1988) in Th cell-dependent antibody production. Both the hemagglutinin titer and number of plaque-forming cells that formed in response to primary immunization with sRBC were decreased in NE-depleted mice when compared with NE-intact mice, but the secondary response to antigen in these mice was unchanged (Kasahara et al., 1977a; 1977b), suggesting that NE was needed for the development of an optimal primary antibody response but not the secondary response. However, the secondary antibody response was suppressed when 6-OHDA was administered at the same time as the secondary exposure to antigen, suggesting that the concentration of NE at the time of antigen exposure may be a determining factor in the development of an optimal primary or secondary antibody response. More recently, the level of serum antigen-specific antibody produced by dopamine ß-hydroxylase-deficient mice was significantly lower than the level of antibody produced by B cells in wild-type mice (Alaniz et al., 1999). Thus, these results suggested that NE was needed to produce an optimal level of antibody in vivo after immunization with antigen.

In contrast, NE depletion was also reported to increase the number of antibody-secreting cells after immunization with the T cell—pendent antigen sRBC (Besedovsky et al., 1979). As well, NE depletion in mice increased the number of antibody-forming cells activated by T-independent antigens but in contrast did not alter the number of antibody-secreting cells activated by a T cell-dependent antigen (Miles et al., 1981). Another study reported a strain-specific enhancement in antibody production against a T cell-dependent antigen in NE-depleted C57Bl/6J (Th1-slanted strain) and

Balb/c (Th2-slanted strain) mice (Kruszewska et al., 1995). In this study, the serum levels of Keyhole Limpet Hemocyanin KLH-specific IgM, total IgG, IgG1, and IgG2a were enhanced in NE-depleted C57Bl/6J mice 1-2 weeks postimmunization, whereas only IgG1 was enhanced in NE-depleted Balb/c mice. To address the possibility that the 6-OHDA-displaced NE might affect immune cells before a state of NE depletion was established and before antigen was delivered, another model system had to be developed.

Antigen-specific Th2 and B cells were adoptively transferred into NE-depleted severe combined immunodeficient (scid) mice after the mice that were depleted of NE by 6-OHDA prior to cell transfer (Kohm and Sanders, 1999). Four weeks after the primary immunization, a significantly lower serum level of antigen-specific IgM and IgG1 was measured in NE-depleted mice as compared with NE-intact mice, and this effect was prevented by the administration of a p2AR-selective agonist. Secondary immunization of these mice depleted of NE 9 weeks earlier induced serum levels of antigen-specific IgG1 that were not only lower but also delayed in reaching a maximal level. NE-depletion did not alter T- and B-cell trafficking to the spleen but was found to decrease follicular expansion and germinal center formation in the spleen when compared with NE-intact controls. Taken together, these data suggest that stimulation of the p2AR during the course of a T-dependent immune response is necessary to maintain an optimal level of antibody production during a primary and secondary response in vivo.

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