Homeostatic control of the immune system is dependent on CD4, FoxP3+, NKT or antigen-specific CD4+ or CD8+ regulatory T cells. These regulatory T cells are essential to prevent or mitigate autoimmunity and the immune response to non-self antigens. Herein is an overview of our observations on the inhibition of the induction of splenic CD4 and CD8+ regulatory T cells, thymic and hepatic regulatory T cells by the ablation of the sympathetic nervous system by the neurotoxin 6-hydroxydopamine (6-OHDA). In contrast, sympathectomy with 6-OHDA induces an elevation in CD4, FoxP3+ regulatory T cells in the spleen and lymph nodes that can mitigate the induction of experimental autoimmune encephalomyelitis. We suggest that the sympathetic influence on the activation and maintenance of different regulatory T cells is a major neuronal influence of the immune system that could be a major factor in chronic stress.
A major factor during the course of evolution has been the development of sophisticated defense mechanisms to prevent the growth and/or eliminate invaders foreign to the host. As a consequence, an immune defense mechanism needs to discriminate between self and non-self. This ability to recognize ‘self’ prevents an activity of this powerful defense against ‘self’ that could destroy the host. Moreover, like any defense mechanism, ‘collateral damage’ can occur in immune activity even though the defense is directed towards a ‘foreign’ invader. Therefore, immune mechanisms initiated against any invader must be regulated. Such regulation is effected by:
The elimination of self-reactive lymphocytes. This occurs during the ontogeny of the immune system and can occur if self-reactive cells encounter large amounts of self-antigen.
The creation of ‘immune privileged’ sites where immune reactions are less likely to occur. Such sites are particularly critical for sensitive tissue such as the eye and the brain.
The generation of regulatory cells that specifically eliminate or inhibit cells that respond to self-antigens that were not eliminated during development. These cells serve as an added protective mechanism for self-reactive cells that ‘escaped’ central elimination during development. These regulatory cells may also modulate immune responses to non-self to mitigate ‘collateral damage’.
Monocytes may serve an innate regulatory function but additionally function in adaptive immunoregulation by participating in the induction of adaptive regulatory T cells. Three T cell types comprise the ‘adaptive’ regulatory (cell) system: CD4+,CD25+ T cells that express the forkhead box P3 transcription factor FoxP3, (Treg); T cells expressing a marker for ‘natural killer’ cells (NKT cell) and CD8+ T cells [1-3]. ‘Natural’ CD4+, FoxP3+ Treg do not require antigenic stimulation. Additionally, antigen-activated effector T cells can be ‘converted’ to a Treg phenotype (so called ‘inducible’ or i-Treg) by antigen, transforming growth factor (TGF)-beta, and IL-6 or IL-17 .
The suppression of the induction of effector T cells mediated by CD4, FoxP3+ T cells is not antigen-specific and may be mediated in part by the transfer of cyclic adenosine monophoshate (cAMP) or TGF-beta to the effector cells [5-7] by the effector cells. NKT cells and antigen-specific CD4+ T cells participate in the activation of CD8+ regulatory T cells that are antigen-specific, but unlike CD4+, FoxP3+ Treg, suppress activated T cells . Most antigen-specific regulatory T cells are amplified by an immune response to regulate that response and act to modulate a future, deleterious response. However, such a regulatory response could mitigate defense against an infectious agent. Additionally, since the immune response can exert an influence on the sensory or sympathetic nervous system (SNS) [8,9], regulation of an immune response could impact on homeostatic neuronal function.
Sympathetic influence on regulatory T cells: The induction of antigen-specific CD8+ regulatory T cells
The seminal views of Selye  first brought attention to neuro-immune interactions. That the central and peripheral nervous system could influence the immune system is not surprising considering the extensive innervation of central and peripheral lymphoid organs. Moreover, lymphocytes and monocytes that comprise adaptive and innate immunity express receptors for neurotransmitters/neuropeptides [8,9]. The influence of the SNS on the immune response has been demonstrated by ablation of peripheral sympathetic neurons by the neurotoxin 6-hydroxydopamine (6-OHDA) that when administered peripherally depletes norepinephrine (NE) levels in the lymphoid organs [8,11-15]. Since 6-OHDA does not cross the Blood Brain Barrier (BBB), peripheral administration of 6-OHDA does not affect catecholamine levels in the Central Nervous System (CNS) although peripheral catecholamine levels are depleted [8,9,11,13].
In contrast to suppressive effects on cell-mediated immunity, systemic injection of mice or rats with of 6-OHDA enhances the production of IgM and IgG1 antibodies [9,11,14,15 ]. The production of cytokines that promote cell-mediated immunity may be affected by chemical sympathectomy [11,14-16] but this is not always the case [9,17]. However, as discussed below, the SNS exerts an influence on regulatory T cells that could prevent delayed-type hypersensitivity (DTH). Moreover, the swelling of tissue in immunized mice induced by antigen does not occur in 6-OHDA-treated mice [17,18]. The lack of DTH-induced swelling at the site challenged by antigen in immunized, 6-OHDA-treated mice could also be due to an influence of the SNS on the vascular exchange of fluids .
The injection of 6-OHDA directly into the CNS of rats induces cells that transfer the suppression of humoral immunity, or induces an increase in OX8+ cells concomitant with the suppression of Experimental Autoimmune Encephalomyelitis (EAE) (20). However, many previous investigations on the influence of the sympathetic or sensory nervous system on the immune response did not consider SNS effects on regulatory T cells. Accordingly, we began an investigation of an influence of the SNS on the induction and function of regulatory T cells. If the SNS exerts an influence on regulatory T cells, conceivably this influence could impact on the suppressor-effector function of these cells and/or the generation of well-defined regulatory T cells. To specifically investigate the influence of the SNS on regulatory T cells, we first focused on a SNS influence on the generation and function of the regulatory T cells induced by the injection of antigen into the anterior chamber of an eye (intracameral injection) because the anterior chamber is highly innervated by sympathetic neurons. This intracameral injection of antigen induces the antigen-specific suppression of cell-mediated immunity and the antigen-induced production of IgG2 (but not IgG1 and IgM) antibodies [1,21]. Suppression is mediated by antigen-specific splenic CD4+ T cells that induce antigen-specific CD8+ T cells that effect the suppression of activated effector T cells [22-24].
The induction of the CD8+ T cells requires the participation of thymic and peripheral T cells that express a cell surface marker of natural killer cells (NKT cells). All of these lymphocytes are induced by circulating F4/80+ monocytes believed to be derived from the eye [25,26]. Preliminary evidence from our laboratory suggests that these monocytes are circulating monocytes that transited the eye in response to the ocular injection and recirculate to the thymus and spleen. As summarized in Fig. 1, the generation of regulatory T cells by Anterior Chamber-Associated Immune Deviation (ACAID) could potentially be influenced by the SNS at several steps. The induction of ACAID requires the circulation and homing of monocytes to the eye, thymus and spleen and lymphocytes to the spleen. Therefore, vascular changes that impact on the movement of these cells would affect ACAID. Moreover, if the maintenance or function of the cells requires neurotransmitters/neuropeptides produced by the SNS, ablation of the SNS could affect the generation and/or function of these cells.
Figure 1. Induction of Anterior Chamber-Associated Immune Deviation (ACAID). The injection of antigen into the anterior chamber of the eye induces the infiltration of circulating F4/80+ monocytes into the anterior chamber. These infiltrated monocytes acquire the antigen, possibly from antigen presenting cells in the iris, are exposed to TGF-beta in aqueous humor and then re-enter the circulation. Once in the circulation the monocytes migrate to the thymus and spleen where they activate thymic regulatory NKT cells and antigen-specific splenic regulatory CD4+ and CD8+ regulatory T cells. Sympathetic neurons could influence TGF-beta levels in aqueous humor in the anterior chamber required to ‘convert’ infiltrating monocytes to a suppressive phenotype, the activation of NKT regulatory thymocytes and peripheral NKT cells.
Because the ablation of the SNS by 6-OHDA prevents the induction of delayed-type hypersensitivity, we used an adoptive transfer assay to measure the effect of sympathectomy by 6-OHDA on the generation of regulatory T cells induced by the intracameral injection of antigen. The cell-mediated, antigen-specific suppression of the swelling induced by delayed-type hypersensitivity (DTH) is mediated specifically by CD8+regulatory T cells induced by the intracameral injection of antigen [27,28]. In the local transfer of suppression assay, spleen cells recovered from donors that received an intracameral injection of antigen are injected into a site in mice immunized to the same antigen as that used for the intracameral injection. These recipient mice are then challenged at that site with the same antigen as that used for immunization to elicit the swelling at the site characteristic of a DTH reaction. In the absence of the injection of regulatory cells, the antigenic challenge will induce in the immunized mice a swelling characteristic of a DTH reaction. The injected CD8+ spleen cells induced by the intracameral injection of antigen inhibit the DTH-induced swelling [21,24,27]. Using this assay we observed that these CD8+ splenic regulatory T cells were not induced in 6-OHDA-treated mice that received an intracameral injection of antigen and immunization .
To determine whether the SNS influences the induction and/or function of the splenic regulatory-effector cells induced by the injection of antigen into the anterior chamber we recovered peripheral blood monocytes (PBMNC) that induce the splenic suppressor-effector lymphocytes of ACAID. These monocytes, recovered from mice receiving an intracameral injection of antigen induce splenic regulatory effector cells when injected intravenously into naïve recipients [21,25,26].
We observed no effect of sympathetic ablation with 6-OHDA on the generation of these circulating monocytes . Although the eye is heavily innervated by sympathetic neurons, these results suggest that the acute ablation of sympathetic neurons does not affect the migration of monocytes to the anterior chamber after the intracameral injection of antigen required to induce regulatory T cells. However, whether 6-OHDA penetrates the blood/eye barrier is not known. In contrast, it has been shown that the selective removal of sympathetic innervation of the eye by surgical removal of the cervical sympathetic ganglion reduced levels of TGF-beta in aqueous humor, and prevented the induction of the suppression of delayed-type hypersensitivity induced by the intracameral injection of antigen . Here the sympathectomy is localized to the eye suggesting that the elimination of ocular sympathetic innervation affects a site that generates circulating cells that induce the activation of peripheral CD8+ regulatory T cells.
The induction of ACAID-transmitting monocytic cells requires the transit of circulating cells through the anterior chamber back to the circulation [30,31]. Circulating monocytes are recruited to the anterior chamber in response to the trauma of injection. Moreover, it is probable that TNF-alpha in aqueous humor required to induce ACAID  would be depleted by sympathetic ganglionectomy since stimulation of sympathetic neurons induces the release of inflammatory cytokines . Although the migration of monocytic cells to the anterior chamber of cervical ganglionectomized mice after the intracameral injection of antigen was not investigated, it is likely that the TGF-beta-induced conversion of F4/80+ monocytes to a suppressive phenotype [21,25] did not occur due to a lack of TGF-beta in the aqueous humor. However, levels of TGF-beta in aqueous humor may not be reduced sufficiently two days after the i.p. injection of 6-OHDA, while TGF-beta may be reduced in aqueous humor during the recovery of mice for one week after surgical ganglionectomy.
Circulating monocytes that induce regulatory lymphocytes after the intracameral injection of antigen migrate to the thymus and spleen and interact with NKT-lymphocytes, B-lymphocytes, CD4+ and CD8+ T cells to induce regulatory-effector T cells [1,21,35]. Central to this induction are NKT cells derived from the thymus [22,23] and the periphery [24,35]. The number of regulatory hepatic natural killer T cells (NKT) cells are diminished in 6-OHDA-treated mice as well as the ability of thymic NKT cells to induce the generation of splenic CD8+regulatory T cells after the injection of antigen into the anterior chamber of an eye . Because the maintenance of hepatic NKT cells requires norepinephrine , the loss of norepinephrine due to sympathectomy with 6-OHDA could impact on the maintenance and/or function of both thymic and peripheral NKT cells necessary to induce the CD8+ regulatory T cells after the intracameral injection of antigen.
The effect of sympathectomy by 6-OHDA on the generation of splenic regulatory effector T cells was investigated further by injecting regulatory thymocytes induced by the intracameral injection of antigen into mice that had been sympathectomized by the injection of 6-OHDA. We asked whether the transfer of thymocytes induced by the intracameral injection of antigen into mice sympathectomized by 6-OHDA would ‘rescue’ the induction of regulatory cells induced by intracameral injection of antigen . However, thymocytes induced by the intracameral injection of antigen did not induce splenic regulatory effector T cells when injected into mice sympathectomized by 6-OHDA. Since these regulatory thymocytes do not become regulatory effector T cells , these results suggested that peripheral CD4+ regulatory T cells induced by an intracameral injection of antigen are also affected by sympathectomy with 6-OHDA. Other neuropeptides produced by the SNS; neuropeptide Y (NPY) , and tissue plasminogen activator  might also influence regulatory T cells directly or indirectly.
CD4, FoxP3+ regulatory T cells (Treg)
The influence of the SNS on the induction of thymic and splenic regulatory T cells by the intracameral injection of antigen indicated a specific role for the SNS in a highly specialized type of antigen-induced regulatory T cells. In addition to these cells, the immune system is regulated by peripheral T cells expressing the cell surface markers CD4 and CD25 (part of the receptor for IL-2) and the transcription factor FoxP3 [3,4]. Many of these cells occur without apparent antigenic stimulation (so-called ‘naïve’ regulatory T cells or Tregs). An effector T cell may also be induced to become a Treg (induced Treg) in the presence of TGF-beta. However, unlike the regulatory T cells induced by the intracameral injection of antigen, the suppression mediated by CD4+, CD25+, FoxP3+ Treg is not antigen-specific.
Because chemical sympathectomy with 6-OHDA prevented the generation of antigen-specific CD8+ regulatory T cells and thymic regulatory NKT cells induced by the intracameral injection of antigen, we investigated the effect of systemic sympathectomy of mice on the number and activity of peripheral CD4+, FoxP3+ regulatory T cells. To our surprise, two days after the injection of 6-OHDA recipient mice had a nearly 2-fold increase in functional splenic and lymph node CD4, FoxP3+ regulatory cells . There was no change in the suppressive ability of these Tregs. This increase in splenic and lymph node Treg is due to an increase in TGF-beta in the spleen and lymph nodes because 6-OHDA treatment did not induce an increase in CD3+, FoxP3+ Treg in mice resistant to signaling by TGF-beta.
Moreover, the induction of EAE is inhibited or reduced in mice that received 6-OHDA before immunization with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide35-55 . Additionally, CD4+, FoxP3+ Treg recovered from mice that received 6-OHDA reduced the induction of EAE. Tregs express tyrosine hydroxylase and catecholamines that might modulate EAE by the induction of intracellular cAMP in effector T cells . The latter report also showed a catecholamine-dependent reduction in Treg. The relationship between catecholamine depletion, an increase in TGF-beta and the source of the TGF-beta in the spleens and lymph nodes of mice receiving 6-OHDA needs to be explored. This could also be due to a response to oxidative injury induced by 6-OHDA. That chemical sympathectomy has also been reported to inhibit or enhance EAE could also be due to timing of sympathectomy vs immunization. An increase in CD4+, FoxP3+ Treg at the time of or before immunization could inhibit the induction of EAE. However, inhibition of the induction of CD8+ Treg could enhance EAE because this population of regulatory T cells more effectively suppresses activated T cells. Preliminary evidence generated by our laboratory (M. Kelsey, S. Bhowmick) suggests that stimulation of the SNS reduces the number of splenic FoxP3+ Treg. Accordingly, stress might induce a disruption in cell-mediated immunoregulation.
The direct modulation of the immune response by the sympathetic nervous system by regulating lymphocytes and antigen-presenting cells impacts all aspects of immunity. However, in addition to these ‘generalized’ effects, a SNS influence on regulatory T cells adds an additional dimension to the neural regulation of immunity. Our experience with investigations on the SNS influence on regulatory T cells has approached regulatory NKT cells, CD4 and CD8+ T cells and CD4, FoxP3+ regulatory T cells (Fig. 2).
Figure 2. Sympathetic influence on all regulatory T cells. Neurotransmitters/neuropeptides produced by the sympathetic nervous system could influence the maintenance, activation and function of regulatory T cells and regulatory monocytes.
The generation of antigen-specific CD4 and CD8+ regulatory T cells via the intracameral injection of antigen utilizes many cell types and depends on the circulation of cells as well as their activation. The inhibition of the induction of splenic regulatory T cells by intracameral injection of antigen by a generalized chemical sympathectomy or by surgical cervical ganglionectomy indicates a sympathetic influence on the generation of systemic regulatory T cells and specifically an influence of the SNS on the ocular environment that would generate regulatory antigen presenting cells that migrated to the anterior chamber in response to the injection of antigen. The loss of TGF-beta in aqueous humor as a result of cervical ganglionectomy could result in a lack of generation of these cells. In support of that contention we have observed that the neutralization of TGF-beta in aqueous humor indeed prevents the generation of circulating monocytes that activate regulatory T cells (R. Pais, RE Cone, unpublished results). The number of regulatory hepatic NKT cells is significantly decreased in mice sympathectomized with 6-OHDA and the activation of thymic regulatory NKT cells by the intracameral injection of antigen is inhibited by chemical sympathectomy.
If, like hepatic NKT cells, the maintenance of thymic NKT cells requires norepinephrine, it is likely that the SNS is essential for the thymic production of regulatory thymocytes essential for the induction of splenic CD4 and CD8+ regulatory T cells. However, regulatory thymocytes induced by the intracameral injection of antigen do not restore the induction of splenic CD4+ and CD8+ regulatory T cells induced by the intracameral injection of antigen. Perhaps the splenic CD4+ NKT cell is derived from the liver as shown for NKT cells required to induce a DTH reaction in immunized mice . Antigen-specific CD8+ T cells suppress activated effector T cells and therefore would be highly effective in regulating an on-going (and perhaps pathologic) immune response to a non-self antigen or an autoimmune response. Therefore, inhibition of the generation of these cells mitigate defense against activated T cells.
Table 1. Effects of sympathectomy with 6-OHDA on splenic immunoregulatory cells
In addition to the influence of the SNS on immune privilege properties and the generation of regulatory T cells that modulate activated T cells, chemical sympathectomy induces a significant rise in CD4, FoxP3+ T cells in the spleen and lymph nodes and a concomitant rise in TGF-beta in the spleen and lymph nodes. Since sympathectomy with 6-OHDA does not increase total splenic and lymph node CD4+ T cells (18) and effector CD4+ T cells treated in vitro with TGF-beta are ‘converted’ to a FoxP3+ Treg phenotype, it is likely that the 6-OHDA-induced increase in splenic and lymph node TGF-beta ‘converted’ effector T cells to Tregs. However, the source of the increased TGF-beta is unknown and we cannot rule out that the rise in TGF-beta was due to oxidative effects on sympathetic neurons by 6-OHDA. In contrast, preliminary data from our laboratory suggests that stimulation of the SNS induces a reduction in Treg (M.Kelsey, S.Bhowmick. RE Cone, unpublished results). Since the SNS is stimulated in stress, one of the effects of stress may be a reduction in regulatory T cells that could lead to an enhanced immune response to non-self antigens or, an exacerbation of autoimmune disease. In aggregate, the influence of the SNS on all types of regulatory T cells (Table 1) adds another dimension to the profound neural regulation of the immune system.
Work by this laboratory described herein was supported by USPHS grants EY017289, EY017537, The University of Connecticut Health Center Research Advisory Committee and the Connecticut Lions Eye Research Foundation.
RE Cone, S Bhowmick – Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030-3105 USA
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Cover image, Left panel: Proposed mechanisms of immunosuppression by regulatory T cells include: production of immunosuppressive IL-10, IL-35 and TGFβ (some TGFβ is membrane bound); production of cytolytic granzyme B; TIGIT-mediated DC production of IL-10 and TGFβ; LAG3 mediated down-regulation of DC function; CTLA4 preventing co-stimulation by by CD80 and CD86 through CD28; inducing expression of IDO by DCs; the cell surface ectoenzymes CD39 and CD73 producing immunosuppressive adenosine; starving effector cells of IL2 through high affinity uptake by regulatory T cell IL2 receptors; inducing IL-10 production by non-regulatory T cells. Abbreviations: CD = cluster of differentiation; DC = dendritic cell; IL = interleukin; TGFβ = transforming growth factor beta; IL2R = IL2 receptor; TIGIT = T cell immunoreceptor with Ig and ITIM domains; LAG-3 = lymphocyte-activation gene 3; IDO = indoleamine 2,3-dioxygenase; CTLA4 = cytotoxic T lymphocyte antigen 4; MHCII = major histocompatibility complex II. Adapted from Vignali DAA. et al., (2008) Nature Immunology 8(7)525-532. Author: Author Gwilz; Credit: Wikimedia, https://commons.wikimedia.org/wiki/File:Mechanisms_of_suppression_by_regulatory_T_cells.png