scholarly journals Type II Activation of Macrophages and Microglia: Roles in T cell biasing and experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
◽  
Sarrabeth Marie Stone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Types ◽  
Type Ii ◽  
Autoimmune Encephalomyelitis ◽  
Th2 Response ◽  
Th1 Response ◽  
Ifn Γ ◽  
Cells Cultured ◽  
Experimental Autoimmune

<p>Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) which causes demyelination and damage to the neuronal axons. MS is a significant health problem in New Zealand, affecting 1 in 1400 people. One of the major cell types involved in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are the proinflammatory subsets of T helper (Th) cells. However, many other cell types are also involved, including macrophages (MΦ) and microglia (MG). MΦ and MG are considered to be important drivers of inflammation during MS; however there is also evidence that indicates these cells can also play a protective role. In the periphery, MΦ can be induced into several activation states. One of these activation states, type II activation, is a regulatory phenotype, producing increased IL-10 and decreased IL-12 compared to classical activation. In vitro type II activation is induced by ligating FcγR with immune complexes (IC) with concurrent stimulation with lipopolysaccharide. Previous research has shown that type II activated MΦ and type II-inducing treatments are protective in EAE.  MΦ activation state affects the way the Th response develops, with classically activated MΦ promoting a Th1 response and type II MΦ promoting a Th2 response. In the current study, the role of MΦ in T cell biasing is investigated further. Type II activated MΦ altered the Th1/Th2 dichotomy away from a Th1 response and towards a Th2 response, as demonstrated by decreased production of IFN-γ and increased levels of CD124. Also, in a novel finding, type II activated MΦ also increased the production of IL-17A from T cells. This study also aimed to elucidate the pathways involved in biasing of the T cell response by classical and type II MΦ by blocking or enhancing specific pathways. It was found that, while the level of IFN-γ (the prototypical Th1 cytokine) was largely dependent on the levels of IL-10 and IL-12, IL-17A and CD124 expression appeared to be independent of these two cytokines. Type II MΦ have decreased expression of CD40 and PD-L1, it was found that these pathways are not strongly involved in T cell biasing by type II MΦ.  While it is acknowledged that MG can be pathogenic and protective, the direct effect type II activating treatments have on MG is unknown. In order to investigate whether MG can also be type II activated, MG were isolated from the CNS of adult mice their phenotype under different activating condition was assessed. Under type II activating conditions MG produced less IL-12 and more IL-10, suggesting type II activation is occurring. In addition, in MG:T cell co-cultures, T cells cultured with classical or type II activated MG have similar, but not identical, profiles to T cells cultured with MΦ. Type II activated MΦ induced increases in CD124 and IL-17A from T cells, however, all MG activation states induced similar levels of IFN-γ.  To determine the effect of type II activating treatments in vivo bone marrow chimeric mice were created using mice congenic for CD45, which allow MG to be distinguished from invading cells. Treatment of mice with the IC before and during EAE results in decrease the incidence and severity of disease. IC treatments altered both the peripheral and the CNS immune environments. Despite inducing protection, IC treatments induced an increase in IL-17A in the peripheral immune system. In the brain, a population of resident cells that are CD45(int)CD11b positive, and are likely to be CNS associated MΦexpress decreased levels of MHC class II, suggesting a decreased ability to interact with T cells. Furthermore, parenchymal MG from the brains of IC treated animals have different levels of Iba1 compared to those from untreated animals, suggesting differential activation. Overall the data suggests that IC treatment induces a change in the activation state of CNS resident immune cells, that is likely to be protective in EAE.</p>

scholarly journals Type II Activation of Macrophages and Microglia: Roles in T cell biasing and experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
◽  
Sarrabeth Marie Stone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Types ◽  
Type Ii ◽  
Autoimmune Encephalomyelitis ◽  
Th2 Response ◽  
Th1 Response ◽  
Ifn Γ ◽  
Cells Cultured ◽  
Experimental Autoimmune

<p>Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) which causes demyelination and damage to the neuronal axons. MS is a significant health problem in New Zealand, affecting 1 in 1400 people. One of the major cell types involved in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are the proinflammatory subsets of T helper (Th) cells. However, many other cell types are also involved, including macrophages (MΦ) and microglia (MG). MΦ and MG are considered to be important drivers of inflammation during MS; however there is also evidence that indicates these cells can also play a protective role. In the periphery, MΦ can be induced into several activation states. One of these activation states, type II activation, is a regulatory phenotype, producing increased IL-10 and decreased IL-12 compared to classical activation. In vitro type II activation is induced by ligating FcγR with immune complexes (IC) with concurrent stimulation with lipopolysaccharide. Previous research has shown that type II activated MΦ and type II-inducing treatments are protective in EAE.  MΦ activation state affects the way the Th response develops, with classically activated MΦ promoting a Th1 response and type II MΦ promoting a Th2 response. In the current study, the role of MΦ in T cell biasing is investigated further. Type II activated MΦ altered the Th1/Th2 dichotomy away from a Th1 response and towards a Th2 response, as demonstrated by decreased production of IFN-γ and increased levels of CD124. Also, in a novel finding, type II activated MΦ also increased the production of IL-17A from T cells. This study also aimed to elucidate the pathways involved in biasing of the T cell response by classical and type II MΦ by blocking or enhancing specific pathways. It was found that, while the level of IFN-γ (the prototypical Th1 cytokine) was largely dependent on the levels of IL-10 and IL-12, IL-17A and CD124 expression appeared to be independent of these two cytokines. Type II MΦ have decreased expression of CD40 and PD-L1, it was found that these pathways are not strongly involved in T cell biasing by type II MΦ.  While it is acknowledged that MG can be pathogenic and protective, the direct effect type II activating treatments have on MG is unknown. In order to investigate whether MG can also be type II activated, MG were isolated from the CNS of adult mice their phenotype under different activating condition was assessed. Under type II activating conditions MG produced less IL-12 and more IL-10, suggesting type II activation is occurring. In addition, in MG:T cell co-cultures, T cells cultured with classical or type II activated MG have similar, but not identical, profiles to T cells cultured with MΦ. Type II activated MΦ induced increases in CD124 and IL-17A from T cells, however, all MG activation states induced similar levels of IFN-γ.  To determine the effect of type II activating treatments in vivo bone marrow chimeric mice were created using mice congenic for CD45, which allow MG to be distinguished from invading cells. Treatment of mice with the IC before and during EAE results in decrease the incidence and severity of disease. IC treatments altered both the peripheral and the CNS immune environments. Despite inducing protection, IC treatments induced an increase in IL-17A in the peripheral immune system. In the brain, a population of resident cells that are CD45(int)CD11b positive, and are likely to be CNS associated MΦexpress decreased levels of MHC class II, suggesting a decreased ability to interact with T cells. Furthermore, parenchymal MG from the brains of IC treated animals have different levels of Iba1 compared to those from untreated animals, suggesting differential activation. Overall the data suggests that IC treatment induces a change in the activation state of CNS resident immune cells, that is likely to be protective in EAE.</p>

scholarly journals Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function

2007 ◽  
Vol 204 (7) ◽  
pp. 1691-1702 ◽  
Author(s):  
Sheng Xiao ◽  
Nader Najafian ◽  
Jay Reddy ◽  
Monica Albin ◽  
Chen Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Dual Function ◽  
Inhibitory Antibody ◽  
Autoimmune Encephalomyelitis ◽  
Th2 Response ◽  
Cell Responses ◽  
Ifn Γ

It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti–Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-γ and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti–Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-γ and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti–Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged.

scholarly journals Activation of Natural Killer T Cells Potentiates or Prevents Experimental Autoimmune Encephalomyelitis

2001 ◽  
Vol 194 (12) ◽  
pp. 1789-1799 ◽  
Author(s):  
Alex W. Jahng ◽  
Igor Maricic ◽  
Brian Pedersen ◽  
Nicolas Burdin ◽  
Olga Naidenko ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Basic Protein ◽  
Autoimmune Encephalomyelitis ◽  
Nk T Cells ◽  
Ifn Γ ◽  
Nk T Cell ◽  
Experimental Autoimmune

Natural killer (NK) T cells recognize lipid antigens in the context of the major histocompatibility complex (MHC) class 1–like molecule CD1 and rapidly secrete large amounts of the cytokines interferon (IFN)-γ and interleukin (IL)-4 upon T cell receptor (TCR) engagement. We have asked whether NK T cell activation influences adaptive T cell responses to myelin antigens and their ability to cause experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. While simultaneous activation of NK T cells with the glycolipid α-galactosylceramide (α-GalCer) and myelin-reactive T cells potentiates EAE in B10.PL mice, prior activation of NK T cells protects against disease. Exacerbation of EAE is mediated by an enhanced T helper type 1 (Th1) response to myelin basic protein and is lost in mice deficient in IFN-γ. Protection is mediated by immune deviation of the anti-myelin basic protein (MBP) response and is dependent upon the secretion of IL-4. The modulatory effect of α-GalCer requires the CD1d antigen presentation pathway and is dependent upon the nature of the NK T cell response in B10.PL or C57BL/6 mice. Because CD1 molecules are nonpolymorphic and remarkably conserved among different species, modulation of NK T cell activation represents a target for intervention in T cell–mediated autoimmune diseases.

scholarly journals Mgat5 Deficiency in T Cells and Experimental Autoimmune Encephalomyelitis

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Ani Grigorian ◽  
Michael Demetriou
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Demyelinating Disease ◽  
Cell Receptor ◽  
Protein Glycosylation ◽  
Autoimmune Encephalomyelitis ◽  
Glycosylation Pathway ◽  
Experimental Autoimmune ◽  
Surface Glycoproteins

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease initiated by autoreactive T cells. Mgat5, a gene in the Asn (N-) linked protein glycosylation pathway, associates with MS severity and negatively regulates experimental autoimmune encephalomyelitis (EAE) and spontaneous inflammatory demyelination in mice. N-glycan branching by Mgat5 regulates interaction of surface glycoproteins with galectins, forming a molecular lattice that differentially controls the concentration of surface glycoproteins. T-cell receptor signaling, T-cell proliferation, TH1 differentiation, and CTLA-4 endocytosis are inhibited by Mgat5 branching. Non-T cells also contribute to MS pathogenesis and express abundant Mgat5 branched N-glycans. Here we explore whether Mgat5 deficiency in myelin-reactive T cells is sufficient to promote demyelinating disease. Adoptive transfer of myelin-reactive Mgat5−/− T cells into Mgat5+/+ versus Mgat5−/− recipients revealed more severe EAE in the latter, suggesting that Mgat5 branching deficiency in recipient naive T cells and/or non-T cells contribute to disease pathogenesis.

scholarly journals TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

2017 ◽  
Vol 114 (8) ◽  
pp. E1480-E1489 ◽  
Author(s):  
Dominika Lukas ◽  
Nir Yogev ◽  
Junda M. Kel ◽  
Tommy Regen ◽  
Ilgiz A. Mufazalov ◽  
...  
Keyword(s):  
T Cells ◽  
Tolerance Induction ◽  
Autoimmune Encephalomyelitis ◽  
Elevated Expression ◽  
The Central Nervous System ◽  
Smad7 Expression ◽  
Ifn Γ ◽  
Tolerogenic Function ◽  
Anti Inflammatory Cytokine ◽  
Experimental Autoimmune

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8+CD103+DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

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