The role of T cell subsets in experimental autoimmune encephalomyelitis
Citation:
Sarah Edwards, 'The role of T cell subsets in experimental autoimmune encephalomyelitis', [thesis], Trinity College (Dublin, Ireland). School of Biochemistry and Immunology, 2015Abstract:
Multiple Sclerosis (MS) is a chronic, demyelinating disease which affects the central nervous system (CNS) resulting in progressive cognitive decline and physical disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS used to understand the cellular and molecular mechanisms underlying the disease. A greater understanding of disease pathogenesis can aid in the discovery of novel disease targets and more effective therapies for MS. Infection with viral or bacterial pathogens has been linked with the development of MS, while infection with helminth parasites has been associated with protection against the symptoms of MS and other autoimmune diseases. Here, the murine model of MS, EAE was used to examine the effect of infection with the respiratory pathogen Bordetella pertussis on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-γ+ and IFN-γ+IL-17+ CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells and enhanced the frequency of IL-10-producing CD25-Foxp3+/-CD4+ T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10-/- mice. The findings of the present study demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. IL-17-producing T cells play a key pathogenic role in many autoimmune disorders, including MS and psoriasis, and are now major drug targets for these diseases. γδ T cells and CD4 T cells are the main sources of IL-17 during inflammation and host immunity. The current study and others have shown that IL-17-secreting Vγ4+ γδ T cells are found at a high frequency in the CNS of mice with EAE. This thesis describes a novel subtype of T cells distinct from conventional αβ or γδ T cells that co-express Vγ4, TCRα and TCRβ, but not TCRδ, and play a critical pathogenic role in CNS autoimmunity. TCRβ-expressing Vγ4+ cells co-express CD4 and CD8 and constitute around 8-10% of Vγ4+ cells in the spleen, lymph nodes, lungs and liver. These cells are present in WT and TCRδ-/- mice but not in TCRα-/- or TCRβ-/- mice. Co- expression of α, β and γ chains was confirmed at the molecular level, revealing a restricted Vγ
repertoire with more heterogeneous Vα and Vβ usage. αβVγ4 T cells express IL-1R1, IL-23R, CD4, CD73, ICOS, CD44, CCR6 and α4β1. Furthermore, these cells secrete IL-17A and IL- 22, following stimulation with IL-1β and IL-23 and respond to autoantigens when purified from mice with EAE. Depletion of Vγ4+ cells from either WT or TCRδ-/- mice dramatically attenuated EAE, and this effect was associated with a significant reduction in MOG-specific IL-17, IFN-γ, GM-CSF and IL-22 and CNS-infiltrating conventional Th17 cells. The data demonstrate that αβVγ4 T cells infiltrate the CNS as early as day 3 during EAE. These findings identify a novel population of T cells that express Vγ4 and αβ TCRs which play a critical role in autoimmunity through the activation of Th17 cells.
Multiple Sclerosis (MS) is a chronic, demyelinating disease which affects the central nervous system (CNS) resulting in progressive cognitive decline and physical disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS used to understand the cellular and molecular mechanisms underlying the disease. A greater understanding of disease pathogenesis can aid in the discovery of novel disease targets and more effective therapies for MS. Infection with viral or bacterial pathogens has been linked with the development of MS, while infection with helminth parasites has been associated with protection against the symptoms of MS and other autoimmune diseases. Here, the murine model of MS, EAE was used to examine the effect of infection with the respiratory pathogen Bordetella pertussis on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-γ+ and IFN-γ+IL-17+ CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells and enhanced the frequency of IL-10-producing CD25-Foxp3+/-CD4+ T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10-/- mice. The findings of the present study demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. IL-17-producing T cells play a key pathogenic role in many autoimmune disorders, including MS and psoriasis, and are now major drug targets for these diseases. γδ T cells and CD4 T cells are the main sources of IL-17 during inflammation and host immunity. The current study and others have shown that IL-17-secreting Vγ4+ γδ T cells are found at a high frequency in the CNS of mice with EAE. This thesis describes a novel subtype of T cells distinct from conventional αβ or γδ T cells that co-express Vγ4, TCRα and TCRβ, but not TCRδ, and play a critical pathogenic role in CNS autoimmunity. TCRβ-expressing Vγ4+ cells co-express CD4 and CD8 and constitute around 8-10% of Vγ4+ cells in the spleen, lymph nodes, lungs and liver. These cells are present in WT and TCRδ-/- mice but not in TCRα-/- or TCRβ-/- mice. Co- expression of α, β and γ chains was confirmed at the molecular level, revealing a restricted Vγ
repertoire with more heterogeneous Vα and Vβ usage. αβVγ4 T cells express IL-1R1, IL-23R, CD4, CD73, ICOS, CD44, CCR6 and α4β1. Furthermore, these cells secrete IL-17A and IL- 22, following stimulation with IL-1β and IL-23 and respond to autoantigens when purified from mice with EAE. Depletion of Vγ4+ cells from either WT or TCRδ-/- mice dramatically attenuated EAE, and this effect was associated with a significant reduction in MOG-specific IL-17, IFN-γ, GM-CSF and IL-22 and CNS-infiltrating conventional Th17 cells. The data demonstrate that αβVγ4 T cells infiltrate the CNS as early as day 3 during EAE. These findings identify a novel population of T cells that express Vγ4 and αβ TCRs which play a critical role in autoimmunity through the activation of Th17 cells.
Multiple Sclerosis (MS) is a chronic, demyelinating disease which affects the central nervous system (CNS) resulting in progressive cognitive decline and physical disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS used to understand the cellular and molecular mechanisms underlying the disease. A greater understanding of disease pathogenesis can aid in the discovery of novel disease targets and more effective therapies for MS. Infection with viral or bacterial pathogens has been linked with the development of MS, while infection with helminth parasites has been associated with protection against the symptoms of MS and other autoimmune diseases. Here, the murine model of MS, EAE was used to examine the effect of infection with the respiratory pathogen Bordetella pertussis on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-γ+ and IFN-γ+IL-17+ CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells and enhanced the frequency of IL-10-producing CD25-Foxp3+/-CD4+ T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10-/- mice. The findings of the present study demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. IL-17-producing T cells play a key pathogenic role in many autoimmune disorders, including MS and psoriasis, and are now major drug targets for these diseases. γδ T cells and CD4 T cells are the main sources of IL-17 during inflammation and host immunity. The current study and others have shown that IL-17-secreting Vγ4+ γδ T cells are found at a high frequency in the CNS of mice with EAE. This thesis describes a novel subtype of T cells distinct from conventional αβ or γδ T cells that co-express Vγ4, TCRα and TCRβ, but not TCRδ, and play a critical pathogenic role in CNS autoimmunity. TCRβ-expressing Vγ4+ cells co-express CD4 and CD8 and constitute around 8-10% of Vγ4+ cells in the spleen, lymph nodes, lungs and liver. These cells are present in WT and TCRδ-/- mice but not in TCRα-/- or TCRβ-/- mice. Co- expression of α, β and γ chains was confirmed at the molecular level, revealing a restricted Vγ
repertoire with more heterogeneous Vα and Vβ usage. αβVγ4 T cells express IL-1R1, IL-23R, CD4, CD73, ICOS, CD44, CCR6 and α4β1. Furthermore, these cells secrete IL-17A and IL- 22, following stimulation with IL-1β and IL-23 and respond to autoantigens when purified from mice with EAE. Depletion of Vγ4+ cells from either WT or TCRδ-/- mice dramatically attenuated EAE, and this effect was associated with a significant reduction in MOG-specific IL-17, IFN-γ, GM-CSF and IL-22 and CNS-infiltrating conventional Th17 cells. The data demonstrate that αβVγ4 T cells infiltrate the CNS as early as day 3 during EAE. These findings identify a novel population of T cells that express Vγ4 and αβ TCRs which play a critical role in autoimmunity through the activation of Th17 cells.
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Grant Number
PRTLI
Author: Edwards, Sarah
Advisor:
Mills, Kingston H. G.Qualification name:
Doctor of Philosophy (Ph.D.)Publisher:
Trinity College (Dublin, Ireland). School of Biochemistry and ImmunologyNote:
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