The Immunosuppressive Agent 15-deoxyspergualin Functions by Inhibiting Cell Cycle Progression and Cytokine Production Following Naive T Cell Activation

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2002  |  Pubmed ID: 12391212

Immunosuppressive agents are commonly used in the prevention of graft rejection following transplantation and in the treatment of autoimmunity. In this study, we examined the immunosuppressive mechanism of the drug 15-deoxyspergualin (DSG), which has shown efficacy in the enhancement of graft survival and in the treatment of autoimmunity. Using a murine model of chronic relapsing and remitting experimental autoimmune encephalomyelitis, we were able to demonstrate that DSG both delayed and reduced the severity of experimental autoimmune encephalomyelitis. Subsequent in vitro studies to examine the mechanism of immune suppression showed that DSG was not able to inhibit early activation of naive CD4 T cells, but DSG did effectively inhibit the growth of naive CD4 T cells after activation. An analysis of cell proliferation and cell cycle showed that DSG treatment led to a block in cell cycle progression 2-3 days following Ag stimulation. In addition, DSG treatment inhibited the production of IFN-gamma by Th1 effector T cells. These studies suggest that CD4 T cells are a predominant target for DSG and the immunosuppressive effects of the drug may result from reduced CD4 T cell expansion and decreased polarization into IFN-gamma-secreting Th1 effector T cells in the induction of certain autoimmune disorders.

Gamma Delta T Cell Regulation of IFN-gamma Production by Central Nervous System-infiltrating Encephalitogenic T Cells: Correlation with Recovery from Experimental Autoimmune Encephalomyelitis

Journal of Immunology (Baltimore, Md. : 1950). Aug, 2004  |  Pubmed ID: 15265886

Interferon-gamma has been shown to be important for the resolution of inflammation associated with CNS autoimmunity. Because one of the roles of gamma delta T cells is the regulation of inflammation, we asked whether gamma delta T cells were able to regulate CNS inflammation using the autoimmune disease mouse model experimental autoimmune encephalomyelitis (EAE). We show that the presence of gamma delta T cells was needed to promote the production of IFN-gamma by both CD4 and CD8 T cells in the CNS before the onset of EAE. This regulation was shown to be independent of the ability of gamma delta T cells to produce IFN-gamma, and was specific to T cells in the CNS, as no alterations in IFN-gamma production were detectable in gamma delta T cell-deficient mice in the spleen and lymph nodes of mice with EAE or following immunization. Analysis of TCR gamma delta gene usage in the CNS showed that the only TCR delta V gene families present in the CNS before EAE onset are from the DV7s6 and DV105s1 gene families. We also show that the primary IFN-gamma-producing cells in the CNS are the encephalitogenic T cells, and that gamma delta T cell-deficient mice are unable to resolve EAE disease symptoms like control mice, thus exhibiting a long-term chronic disease course similar to that observed in IFN-gamma-deficient mice. These data suggest that CNS resident gamma delta T cells promote the production of IFN-gamma by encephalitogenic T cells in the CNS, which is ultimately required for the recovery from EAE.

Gamma Delta T Cells Regulate the Extent and Duration of Inflammation in the Central Nervous System by a Fas Ligand-dependent Mechanism

Journal of Immunology (Baltimore, Md. : 1950). Apr, 2005  |  Pubmed ID: 15814692

Gamma delta T cells have been shown to regulate immune responses associated with inflammation, but the mechanism of this regulation is largely unknown. Using the experimental autoimmune encephalomyelitis (EAE) model of the human CNS autoimmune disease multiple sclerosis, we demonstrate that gamma delta T cells are important regulators of CNS inflammation. This was shown using gamma delta T cell-deficient mice that were unable to recover from EAE. The chronic disease was accompanied by a prolonged presence of both macrophages and lymphocytes in the CNS. This extended inflammatory response was due to alterations in both cell proliferation and death. In mice lacking gamma delta T cells, proliferation of encephalitogenic T cells was 3-fold higher, and caspase activity, indicating apoptosis, was 2-fold lower compared with those in control mice recovering from EAE. gamma delta T cell-deficient mice reconstituted with wild-type gamma delta T cells recovered from EAE and resolved inflammation in the CNS, whereas mice reconstituted with Fas ligand-dysfunctional gamma delta T cells did not. Thus, gamma delta T cells regulate both inflammation in the CNS and disease recovery via Fas/Fas ligand-induced apoptosis of encephalitogenic T cells, and a quick resolution of inflammation in the CNS is essential to prevent permanent damage to the CNS resulting in chronic disease.

Development of a Culture System That Supports Adult Microglial Cell Proliferation and Maintenance in the Resting State

Journal of Immunological Methods. May, 2005  |  Pubmed ID: 15893321

Microglial cells constitute what is considered to be a fixed macrophage population in the central nervous system (CNS), which are broadly implicated in the regulation of neuroinflammation. In the normal adult CNS, microglial cells exist in a resting state characterized by a minimal or negative expression of MHC class II and the co-stimulatory molecules CD80, CD86 and CD40 and exhibit a unique ramified morphology. Microglial cell activation is associated with many inflammatory and neurogenerative CNS pathologies and is characterized by the transformation of resting microglia into cells with a macrophage morphology and up-regulation of MHC class II and co-stimulatory molecules. The cellular and molecular mechanisms required for microglial cell activation and their immunological functions in the adult brain still remain enigmatic, primarily due to the lack of an appropriate culture system that both facilitates microglial survival and expansion in the resting state. Here, we describe a new M-CSF-dependent culture system that overcomes these barriers and allows the long-term proliferation and maintenance of resting adult microglial cells isolated from the CNS. These cultured microglial cells retain their plasticity as indicated by their ability to up-regulate MHC class II and differentiate into cells with a macrophage morphology following the addition of IFN-gamma and GM-CSF, or activated T cells, which produce both cytokines. By measuring the proliferation of the T cells, we were also able to demonstrate that the microglial cells differentiated into fully functional antigen presenting cells. In addition, the replacement of the M-CSF with GM-CSF resulted in the differentiation of microglial cells into cells morphologically and phenotypically similar to dendritic cells. Our microglial cell culture system is the first described that allows the expansion of adult cells in the resting state and will facilitate studies examining the specific mechanisms of microglial cell activation and functions involved in a variety of CNS pathologies.

Epicutaneously Induced TGF-beta-dependent Tolerance Inhibits Experimental Autoimmune Encephalomyelitis

Journal of Neuroimmunology. Jul, 2005  |  Pubmed ID: 15899524

Multiple sclerosis (MS) is a devastating autoimmune disorder of the central nervous system (CNS) with limited treatment modalities. To evaluate the efficacy of epicutaneous (e.c.) tolerance induction in the prevention of CNS autoimmunity, we utilized an animal model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE). We show that application of myelin basic protein (MBP) to the skin prior to the induction of EAE by immunization with MBP protected mice from developing disease. In addition, e.c. application of MBP at the first clinical signs of EAE, also resulted in suppression of disease. This therapeutic effect was transferable to naïve recipients with lymph node cells from MBP-treated mice. These regulatory cells were found to be antigen non-specific, as suppression of EAE also occurred when the foreign antigens OVA or TNP were e.c. applied. The mechanistic basis for the tolerance was found to be the production of TGF-beta by the antigen induced toleragenic regulatory T cells. These data demonstrate that e.c.-induced regulatory T cells are potent inhibitors of antigen-specific T cell responses, and suggest that e.c. tolerization may have potential effectiveness in the treatment of autoimmune disorders.

Microglial Cell Activation and Proliferation Precedes the Onset of CNS Autoimmunity

Journal of Neuroscience Research. Aug, 2005  |  Pubmed ID: 15959904

Microglial cells are central nervous system (CNS) resident cells that are thought to become activated and contribute to the inflammation that occurs in the human autoimmune disease multiple sclerosis (MS). This has never been proven, however, because microglial cells cannot be phenotypically distinguished from peripheral macrophages that accumulate in MS inflammatory lesions. To study the kinetics and nature of microglial cell activation in the CNS, we used the animal model of MS, experimental autoimmune encephalomyelitis (EAE), and induced EAE in bone marrow (BM) chimera mice generated using major histocompatibility complex (MHC)-mismatched donor BM, allowing the separation of microglial cells and peripheral monocytes/macrophages. We found that microglial cell activation was evident before onset of disease symptoms and infiltration of peripheral myeloid cells into the CNS. Activated microglial cells underwent proliferation and upregulated the expression of CD45, MHC class II, CD40, CD86, and the dendritic cell marker CD11c. At the peak of EAE disease, activated microglial cells comprised 37% of the total macrophage and dendritic cell populations and colocalized with infiltrating leukocytes in inflammatory lesions. Our findings thus definitively demonstrate that during EAE, microglial cells become activated early in EAE disease and then differentiate into both macrophages and dendritic-like cells, suggesting they play an active role in the pathogenesis of EAE and MS.

Modulation of the Cannabinoid CB2 Receptor in Microglial Cells in Response to Inflammatory Stimuli

Journal of Neurochemistry. Oct, 2005  |  Pubmed ID: 16086683

The cannabinoid system is known to be important in neuronal regulation, but is also capable of modulating immune function. Although the CNS resident microglial cells have been shown to express the CB2 subtype of cannabinoid receptor during non-immune-mediated pathological conditions, little is known about the expression of the cannabinoid system during immune-mediated CNS pathology. To examine this question, we measured CB2 receptor mRNA expression in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) and, by real-time PCR, found a 100-fold increase in CB2 receptor mRNA expression during EAE onset. We next determined whether microglial cells specifically express the CB2 receptor during EAE, and found that activated microglial cells expressed 10-fold more CB2 receptor than microglia in the resting state. To determine the signals required for the up-regulation of the CB2 receptor, we cultured microglial cells with combinations of gamma-interferon (IFN-gamma) and granulocyte) macrophage-colony stimulating factor (GM-CSF), which both promote microglial cell activation and are expressed in the CNS during EAE, and found that they synergized, resulting in an eight to 10-fold increase in the CB2 receptor. We found no difference in the amount of the CB2 receptor ligand, 2-arachidonylglycerol (2-AG), in the spinal cord during EAE. These data demonstrate that microglial cell activation is accompanied by CB2 receptor up-regulation, suggesting that this receptor plays an important role in microglial cell function in the CNS during autoimmune-induced inflammation.

CD40 Expression by Microglial Cells is Required for Their Completion of a Two-step Activation Process During Central Nervous System Autoimmune Inflammation

Journal of Immunology (Baltimore, Md. : 1950). Feb, 2006  |  Pubmed ID: 16424167

Microglial cells are monocytic lineage cells that reside in the CNS and have the capacity to become activated during various pathological conditions. Although it was demonstrated that activation of microglial cells could be achieved in vitro by the engagement of CD40-CD40L interactions in combination with proinflammatory cytokines, the exact factors that mediate activation of microglial cells in vivo during CNS autoimmunity are ill-defined. To investigate the role of CD40 in microglial cell activation during experimental autoimmune encephalomyelitis (EAE), we used bone marrow chimera mice that allowed us to distinguish microglial cells from peripheral macrophages and render microglial cells deficient in CD40. We found that the first step of microglial cell activation was CD40-independent and occurred during EAE onset. The first step of activation consisted of microglial cell proliferation and up-regulation of the activation markers MHC class II, CD40, and CD86. At the peak of disease, microglial cells underwent a second step of activation, which was characterized by a further enhancement in activation marker expression along with a reduction in proliferation. The second step of microglial cell activation was CD40-dependent and the failure of CD40-deficient microglial cells to achieve a full level of activation during EAE was correlated with reduced expansion of encephalitogenic T cells and leukocyte infiltration in the CNS, and amelioration of clinical symptoms. Thus, our findings demonstrate that CD40 expression on microglial cells is necessary to complete their activation process during EAE, which is important for disease progression.

T-cell-mediated Disruption of the Neuronal Microtubule Network: Correlation with Early Reversible Axonal Dysfunction in Acute Experimental Autoimmune Encephalomyelitis

The American Journal of Pathology. Sep, 2006  |  Pubmed ID: 16936273

During the course of the central nervous system autoimmune disease multiple sclerosis (MS), damage to myelin leads to neurological deficits attributable to demyelination and conduction failure. However, accumulating evidence has indicated that axonal injury is also a predictor of MS clinical disease. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we examined whether axonal dysfunction occurred early in disease and correlated with disease symptoms. We tracked axons during EAE by using transgenic mice that express yellow fluorescent protein (YFP) in neurons. At the onset of disease, we observed a loss of YFP fluorescence in the spinal cord in areas that coincided with immune cell infiltration, before prominent demyelination. These inflammatory lesions also exhibited evidence of axonal injury but not axonal loss. During the recovery phase of EAE, the return of YFP fluorescence occurred in parallel with the resolution of inflammation. Using in vitro cultured neurons expressing YFP, we demonstrated that encephalitogenic T cells alone directed the destabilization of microtubules within neurites, resulting in a change in the pattern of YFP fluorescence. This study provides evidence that encephalitogenic T cells directly cause reversible axonal dysfunction at the onset of neurological deficits during an acute central nervous system inflammatory attack.

IL-10 Signaling is Essential for 1,25-dihydroxyvitamin D3-mediated Inhibition of Experimental Autoimmune Encephalomyelitis

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2006  |  Pubmed ID: 17056528

Multiple sclerosis (MS) results from an aberrant, neuroantigen-specific, T cell-mediated autoimmune response. Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports vitamin D(3) synthesis, we proposed that vitamin D(3) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) may protect against MS. In support of this hypothesis, 1,25-(OH)(2)D(3) strongly inhibited experimental autoimmune encephalomyelitis (EAE). This inhibition required lymphocytes other than the encephalitogenic T cells. In this study, we tested the hypothesis that 1,25-(OH)(2)D(3) might inhibit EAE through the action of IL-10-producing regulatory lymphocytes. We report that vitamin D(3) and 1,25-(OH)(2)D(3) strongly inhibited myelin oligodendrocyte peptide (MOG(35-55))-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene. Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)(2)D(3) to inhibit EAE. The 1,25-(OH)(2)D(3) also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa. Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro-protective functions of sunlight and vitamin D(3). In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D(3) insufficiency, to increase MS risk and severity.

GM-CSF Production by Autoreactive T Cells is Required for the Activation of Microglial Cells and the Onset of Experimental Autoimmune Encephalomyelitis

Journal of Immunology (Baltimore, Md. : 1950). Jan, 2007  |  Pubmed ID: 17182538

Multiple sclerosis (MS) is a CNS autoimmune disease believed to be triggered by T cells secreting Th1-specific proinflammatory cytokines, such as GM-CSF. In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), Th1 but not Th2 cells have been shown to induce disease; however, to date, no single encephalitogenic T cell-derived cytokine has been shown to be required for EAE onset. Because GM-CSF-deficient mice have been shown to be resistant to EAE following immunization with myelin self-Ag, we investigated the cellular source of the required GM-CSF and found that GM-CSF production by encephalitogenic T cells, but not CNS resident or other peripheral cells, was required for EAE induction. Furthermore, we showed that microglial cell activation, but not peripheral macrophage activation, was a GM-CSF-dependent process. Activation of microglial cells by the injection of LPS abrogated the GM-CSF requirement for EAE induction, suggesting that microglial cell activation is required for EAE onset. These data also demonstrate that GM-CSF is a critical Th1 cell-derived cytokine required for the initiation of CNS inflammation associated with EAE, and likely MS.

B Cell Regulation of CD4+CD25+ T Regulatory Cells and IL-10 Via B7 is Essential for Recovery from Experimental Autoimmune Encephalomyelitis

Journal of Immunology (Baltimore, Md. : 1950). Mar, 2007  |  Pubmed ID: 17339439

CD4(+)CD25(+) T regulatory (Treg) cells expressing the Foxp3 transcription factor have been shown to be present in the CNS during the autoimmune disease experimental autoimmune encephalomyelitis (EAE) and can inhibit EAE clinical disease by an IL-10-dependent mechanism. In addition, IL-10 expression in the CNS late in the EAE disease course has been attributed to recovery. However, it is not known how Treg cells and IL-10 expressions are regulated during EAE. We have previously shown a requirement for B cells in recovery from EAE and here investigated whether this was due to a deficiency in Treg cells and IL-10 in the CNS. We found that B cell deficiency resulted in a delay in the emergence of Foxp3-expressing Treg cells and IL-10 in the CNS during EAE, but not in the periphery. Reconstitution with wild-type B cells resulted in disease recovery and normalized IL-10 and Foxp3 expression. However, reconstitution with B7-deficient B cells did not. Furthermore, we show that IL-10 and Foxp3 expression is enhanced in CNS nonencephalitogenic T cells. These data suggest a novel mechanism whereby B cells regulate CD4(+)CD25(+) Treg cells via B7 and subsequently enter the CNS and suppress autoimmune inflammation, mediating recovery.

Direct Suppression of CNS Autoimmune Inflammation Via the Cannabinoid Receptor CB1 on Neurons and CB2 on Autoreactive T Cells

Nature Medicine. Apr, 2007  |  Pubmed ID: 17401376

The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.

CNS-derived Interleukin-4 is Essential for the Regulation of Autoimmune Inflammation and Induces a State of Alternative Activation in Microglial Cells

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2007  |  Pubmed ID: 17913905

Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in neurodegenerative diseases such as multiple sclerosis (MS). We investigated the role of interleukin-4 (IL-4) in regulating CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells. We also found that CNS-resident microglial cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated macrophages (aaMphis), in an IL-4-dependent manner. This aaMphi phenotype extended to the lack of nitric oxide (NO) production by activated microglial cells, which is a marker of classically activated macrophages. We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, macrophages that migrate into the CNS exhibit a dual phenotype. These data indicate that IL-4 production in the CNS is essential for controlling autoimmune inflammation by inducing a microglial cell aaMphi phenotype. Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for microglial cells in the regulation of inflammation in the CNS.

CD4 T Cells: Balancing the Coming and Going of Autoimmune-mediated Inflammation in the CNS

Brain, Behavior, and Immunity. May, 2008  |  Pubmed ID: 18207698

The regulation of the inflammatory response is often viewed as very complex with many cellular players. The type of immune response generated is dependent upon the nature of the immune stimulation. In autoimmunity, one of the most important players is the CD4 T cell. The CD4 T cell lineage consists of a number of phenotypically and functionally distinct subsets. The unique functions of CD4 T cells are often mediated by soluble factors, which shape the nature of the immune response. In a T cell-mediated autoimmune response, such as in multiple sclerosis (MS), the CD4 T cell is thought to orchestrate and drive the immune response resulting in inflammation within the central nervous system (CNS). The extent of the inflammation must be tightly controlled or permanent tissue damage will occur. In MS, progressive debilitating disease is thought to be due to such damage. In addition to promoting inflammation, the CD4 T cell lineage also has the capacity to prevent and downmodulate inflammation. This is accomplished by specific CD4 T regulatory (Treg) cells and other regulatory feedback mechanisms. Thus although the complexity of the immune system is often viewed as too complicated for a nonimmunologist to fully understand, there are patterns that emerge that make the system clearer. One such pattern is the balance that the immune system must always maintain. A weak or slow immune response to a pathogen can lead to sickness and even death, while a too robust or uncontrolled immune response can lead to tissue damage, and for autoimmune diseases, ultimately death. How CD4 T cells maintain this balance will be discussed in the context of the CNS autoimmune disease MS.

IL-13 Induces the Expression of the Alternative Activation Marker Ym1 in a Subset of Testicular Macrophages

Journal of Reproductive Immunology. Jul, 2008  |  Pubmed ID: 18329106

Macrophages are thought to play an important role in the maintenance of immune privilege in the testis, which functions to prevent immune responses to developing sperm. Two populations of macrophages are known to exist in the testis, one of which exhibits immunosuppressive activity. Macrophages that are alternatively activated with either IL-4 or IL-13 have been shown to be anti-inflammatory and promote wound healing. Expression of the Ym1 protein is an established marker of alternatively activated macrophages. Testicular macrophages were examined for expression of Ym1 protein, and it was found to be highly expressed in a subpopulation of CD11b(+) cells. Furthermore, we have shown that Ym1 protein expression in the testis is dependent upon IL-13R signaling, and that IL-13 is produced in the testis. These data suggest that IL-13 plays a role in testicular immune privilege by the maintenance of an alternatively activated macrophage population.

A Case for Regulatory B Cells in Controlling the Severity of Autoimmune-mediated Inflammation in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Journal of Neuroimmunology. Jan, 2011  |  Pubmed ID: 21145597

Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease that results in the presence of inflammatory lesions/plaques associated with mononuclear cell infiltrates, demyelination and axonal damage within the central nervous system (CNS). To date, FDA approved therapies in MS are thought to largely function by modulation of the immune response. Since autoimmune responses require many arms of the immune system, the direct cellular mechanisms of action of MS therapeutics are not definitively known. The mouse model of MS, experimental autoimmune encephalomyelitis (EAE), has been instrumental in deciphering the mechanism of action of MS drugs. In addition, EAE has been widely used to study the contribution of individual components of the immune system in CNS autoimmunity. In this regard, the role of B cells in EAE has been studied in mice deficient in B cells due to genetic ablation and following depletion with a B cell-targeted monoclonal antibody (mAb) (anti-CD20). Both strategies have indicated that B cells regulate the extent of EAE clinical disease and in their absence disease is exacerbated. Thus a new population of "regulatory B cells" has emerged. One reoccurring component of regulatory B cell function is the production of IL-10, a pleiotropic cytokine with potent anti-inflammatory properties. B cell depletion has also indicated that B cells, in particular antibody production, play a pathogenic role in EAE. B cell depletion in MS using a mAb to CD20 (rituximab) has shown promising results. In this review, we will discuss the current thinking on the role of B cells in MS drawing from knowledge gained in EAE studies and clinical trials using therapeutics that target B cells.

Taming of Macrophage and Microglial Cell Activation by MicroRNA-124

Cell Research. Feb, 2011  |  Pubmed ID: 21221133

The Encephalitogenicity of T(H)17 Cells is Dependent on IL-1- and IL-23-induced Production of the Cytokine GM-CSF

Nature Immunology. Jun, 2011  |  Pubmed ID: 21516111

Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) require exposure to IL-23 to become encephalitogenic, but the mechanism by which IL-23 promotes their pathogenicity is not known. Here we found that IL-23 induced production of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in T(H)17 cells and that GM-CSF had an essential role in their encephalitogenicity. Our findings identify a chief mechanism that underlies the important role of IL-23 in autoimmune diseases. IL-23 induced a positive feedback loop whereby GM-CSF secreted by T(H)17 cells stimulated the production of IL-23 by antigen-presenting cells. Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies T(H)17 cells as a crucial source of GM-CSF in autoimmune inflammation.

Unraveling the Complexities of Cannabinoid Receptor 2 (CB2) Immune Regulation in Health and Disease

Immunologic Research. Oct, 2011  |  Pubmed ID: 21626285

It has become clear that the endocannabinoid system is a potent regulator of immune responses, with the cannabinoid receptor 2 (CB2) as the key component due to its high expression by all immune subtypes. CB2 has been shown to regulate immunity by a number of mechanisms including development, migration, proliferation, and effector functions. In addition, CB2 has been shown to modulate the function of all immune cell types examined to date. CB2 is a G(i)-protein-coupled receptor and thus exhibits a complex pharmacology allowing both stimulatory and inhibitory signaling that depends on receptor expression levels, ligand concentration, and cell lineage specificities. Here, we discuss both in vitro and in vivo experimental evidence that CB2 is a potent regulator of immune responses making it a prime target for the treatment of inflammatory diseases.

Cannabinoid Receptor 2 is Critical for the Homing and Retention of Marginal Zone B Lineage Cells and for Efficient T-independent Immune Responses

Journal of Immunology (Baltimore, Md. : 1950). Dec, 2011  |  Pubmed ID: 22048769

The endocannabinoid system has emerged as an important regulator of immune responses, with the cannabinoid receptor 2 (CB2) and its principle ligand 2-archidonoylglycerol playing a major role. How CB2 regulates B cell functions is not clear, even though they express the highest levels of CB2 among immune cell subsets. In this study, we show that CB2-deficient mice have a significant reduction in the absolute number of marginal zone (MZ) B cells and their immediate precursor, transitional-2 MZ precursor. The loss of MZ lineage cells in CB2(-/-) mice was shown to be B cell intrinsic using bone marrow chimeras and was not due to a developmental or functional defect as determined by B cell phenotype, proliferation, and Ig production. Furthermore, CB2(-/-) B cells were similar to wild type in their apoptosis, cell turnover, and BCR and Notch-2 signaling. We then demonstrated that CB2(-/-) MZ lineage B cells were less efficient at homing to the MZ and that their subsequent retention was also regulated by CB2. CB2(-/-) mice immunized with T-independent Ags produced significantly less Ag-specific IgM. This study demonstrates that CB2 positively regulates T-independent immune responses by controlling the localization and positioning of MZ lineage cells to the MZ.