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Principal Investigator: Yisong Wan
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $382,837
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary:
Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammation disease inflicting millions of
people worldwide. It is caused by dysregulated adaptive and innate immunity. CD4 T cells critically contribute
to MS development in humans and EAE development in mice. Particularly, Th17 cells are central to
autoimmune neuroinflammation. To understand the etiology of and develop treatment for MS, one of the main
goals of MS research is to understand how T cell and Th17 cell function are controlled. Transforming growth
factor–β (TGF-β) is instrumental in Th17 cell differentiation and function. Yet it is unclear whether and how
TGF-β superfamily member other than TGF-β controls Th17 cell differentiation in MS/EAE.
Our recent findings revealed novel TGF-β superfamily and related signaling to regulate Th17 cell
function and the development of autoimmune neuroinflammation: (1) SKI protein, a TGF-β signaling
suppressor that is degraded upon TGF-β stimulation, suppresses Th17 cell differentiation in vitro and in vivo,
(2) SKI expression in T cells completely protected mice from EAE, (3) Activin-A, a TGF-β superfamily member
that is closely related to TGF-β, was upregulated during EAE and in activated T cells in inflamed tissues and in
the presence of proinflammatory cytokines, and (4) Activin-A+IL6 induced SKI degradation and the
differentiation of Th17 cells that phenotypically resemble pathogenic- rather than non-pathogenic-Th17 cells to
promote EAE. We therefore hypothesize that TGF-β superfamily member Activin-A is a novel factor distinct
from TGF-β to promote pathogenic Th17 function and autoimmune neuroinflammation through SKI. In this
study, we proposed to reach the following three Aims. AIM 1: Address whether Activin-A is required for Th17
cell function and EAE. AIM 2: Reveal the molecular program of Activin-A induced Th17 cell generation and
function; AIM 3: Investigate the mechanisms underlying SKI controlled Th17 cell function and EAE.
There is a great and yet unmet need in the understanding of how Th17 cell function during autoimmune
neuroinflammation. This study aims to reveal previous unappreciated cellular and molecular mechanisms
underlying TGF-β superfamily signaling in controlling Th17 cell differentiation and function for autoimmunity.
The success of this study will gain critical mechanistic insights into T cell mediated autoimmune
neuroinflammation and shed new light on how to mitigate related disease by targeting TGF-β superfamily
signaling pathways.
Terms: <ALK-5 protein><ALK-5 receptor><ALK5><Activin A Receptor Type II-Like Kinase 53kDa><Activin Receptor-Like Kinase 5><Address><Adopted><Autoimmune><Autoimmune Status><Autoimmunity><Autoregulation><B-Cell Differentiation Factor Gene><B-Cell Stimulatory Factor 2 Gene><BSF-2 Gene><BSF2 Gene><Beta-2 Gene Interferon><Body Tissues><Bone-Derived Transforming Growth Factor><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CSIF><CSIF-10><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Causality><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Critical Paths><Critical Pathways><Cytokine Synthesis Inhibitory Factor><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Development><Differentiation in cell culture><Disease><Disorder><Disseminated Sclerosis><EAE><EYDF><Etiology><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><GM-CSF><Generations><Genes><Genetic><Goals><Granulocyte-Macrophage Colony-Stimulating Factor><HSF Gene><Hepatocyte Stimulatory Factor Gene><Histamine-Producing Cell-Stimulating Factor><Homeostasis><Human><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-10><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-6 Gene><IL10><IL10A><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL6><IL6 gene><Immune><Immune Tolerance><Immunes><Immunologic Tolerance><In vitro cell differentiation><Inflammatory><Innate Immunity><Interleukin 10 Precursor><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-10><Interleukin-17><Interleukin-6 Gene><Intracellular Communication and Signaling><MS treatment><Mediating><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Molecular><Molecular Target><Molgramostin><Multiple Sclerosis><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Oncogene SKI><Pathogenicity><Pathology><Pathway interactions><Persons><Phenotype><Physiological Homeostasis><Platelet Transforming Growth Factor><Proteins><Receptor Protein><Regulator Genes><Research><Role><SKI><SKI gene><SKR4><Serine/Threonine-Protein Kinase Receptor R4><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TC-GM-CSF><TGF B><TGF-beta><TGF-beta type I receptor><TGF-β><TGFBR-1><TGFbeta><TGFβ><Tissues><Transcriptional Regulatory Elements><Transforming Growth Factor Beta Receptor I><Transforming Growth Factor Beta Receptor Type I><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Tumor-Cell Human GM Colony-Stimulating Factor><activate T cells><activin A><adaptive immunity><autoimmune encephalomyelitis><biological signal transduction><causation><cellular differentiation><cytokine><developmental><differentiation in culture><differentiation in vitro><disease causation><effective therapy><effective treatment><erythroid differentiation factor><erythroid differentiation protein><gene signatures><genetic signature><granulocyte macrophage colony stimulating factor><homo-activin A><immune system tolerance><immune unresponsiveness><immunological paralysis><in vitro cellular differentiation><in vivo><insight><insular sclerosis><interest><member><multiple sclerosis therapy><multiple sclerosis treatment><neural inflammation><neuroinflammation><neuroinflammatory><novel><pathway><programs><receptor><regulatory gene><social role><success><thymus derived lymphocyte><trans acting element><v-SKI Avian Sarcoma Viral Oncogene Homolog>