Experimental autoimmune encephalomyelitis (EAE) serves as a model for human multiple sclerosis (MS). Both EAE and MS manifest as a consequence of an inflammatory process within the central nervous system (CNS) that is mediated by cells of the immune system. The disease develops when T regulatory cells (Tregs) are no longer able to control activation of myelin-reactive effector T cells. It is thus crucial to understand why Tregs become unable to keep effector T cells in check and how the myelin-reactive lymphocytes evade such control in order to develop approaches that could contain the disease. Recently, we discovered a novel class of thymic stem cell progenitors expressing IL-13 receptor ?1 (IL-13R?1) that contribute to the development and function of both Tregs and effector T cells. The lineage negative (Lin-) IL-13R?1+ stem cells, which arise in the bone marrow (BM), migrate to the thymus and become early thymic progenitors (ETPs). However, these IL-13R?1+ ETPs do not mature into T lymphocytes. Rather, they give rise to CD11b+ myeloid cells that are retained in the thymus and function as antigen-presenting cells (APCs) that contribute to the selection process of both Tregs and effector T cells. The IL-13R?1+ BM stem cells that do not migrate to the thymus also give rise to IL-13R?1+ myeloid cells as well as dendritic cells (DCs) that likely function as peripheral APCs and contribute to the function of Tregs and effector T cells. The long term objective in this proposal is to define the contribution of IL-13R?1+ ETPs to thymic T cell selection and to determine how the IL-13R?1+ BM stem cell-derived peripheral APCs (myeloid and DCs) regulate the function of the ETP-selected Tregs and effector T cells. The major hypothesis in this proposal postulates that IL-13R?1+ETP-derived myeloid cells function as APCs for thymic selection and display discrepancies among effector and regulatory T cells as well as self versus foreign antigens. Ultimately, the thymic outcome dictates T cell output to the periphery and, in coordination with the IL- 13R?1+ peripheral APCs, regulates myelin-reactivity and EAE.
Three aims are proposed to test these hypotheses.
Aim 1 will define the role IL-13R?1+ETPs play in thymic T cell selection, aim 2 will assess the role IL-13R?1+ ETPs play in the development of peripheral T cell responses and EAE, and aim 3 will determine how IL-13R?1+ Lin- BM stem cells regulate T cell responses and EAE. This study is of high impact because it could yield mechanistic insights useful for the generation of therapeutics against EAE and MS.

Public Health Relevance

The study defines a new class of IL-13R?1+ early thymic progenitors (ETPs) that give rise to thymic myeloid cells rather than T cells, and proposes to delineate the mechanism by which the ETP-derived myeloid cells impact T cell selection and output to the periphery. We expect to determine whether the myeloid cells, which function as antigen presenting cells, play a differential role in the selection of effector versus regulatory T cells and the development of self- versus non-self-reactive T cells. Also, because IL-13R?1+ bone marrow stem cells give rise to myeloid and dendritic cells in the periphery, we will be able to determine how the IL-13R?1+ peripheral APCs impact ETP-mediated selection and control the response of the selected T cells in the periphery. Overall, we expect to shed light on the contribution of IL-13R?1+ stem cells to both central and peripheral tolerance of myelin-reactive T cells and to obtain information useful for the design of approaches against EAE and MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS057194-05
Application #
8574649
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2007-01-01
Project End
2018-03-31
Budget Start
2013-05-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$325,606
Indirect Cost
$106,856
Name
University of Missouri-Columbia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Cascio, Jason A; Khairallah, Marie-Therese; Wan, Xiaoxiao et al. (2014) In trans T cell tolerance exacerbates experimental allergic encephalomyelitis by interfering with protective antibody responses. J Neuroimmunol 266:49-55
Dhakal, Mermagya; Hardaway, John C; Guloglu, Fatma Betul et al. (2014) IL-13R*1 is a surface marker for M2 macrophages influencing their differentiation and function. Eur J Immunol 44:842-55
Cascio, Jason A; Haymaker, Cara L; Divekar, Rohit D et al. (2013) Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance. J Immunol 190:6004-14
Haymaker, Cara L; Guloglu, F Betul; Cascio, Jason A et al. (2012) Bone marrow-derived IL-13Rýý1-positive thymic progenitors are restricted to the myeloid lineage. J Immunol 188:3208-16
Divekar, Rohit D; Haymaker, Cara L; Cascio, Jason A et al. (2011) T cell dynamics during induction of tolerance and suppression of experimental allergic encephalomyelitis. J Immunol 187:3979-86
Zhang, Jinping; Lee, Sang-Myeong; Shannon, Stephen et al. (2009) The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119:3048-58
Yu, Ping; Haymaker, Cara L; Divekar, Rohit D et al. (2008) Fetal exposure to high-avidity TCR ligand enhances expansion of peripheral T regulatory cells. J Immunol 181:73-80