Experimental allergic encephalomyelitis (EAE), an inflammatory disease within the central nervous system (CNS) is used as an animal model for human multiple sclerosis (MS). The involvement of the immune system in these diseases is beyond doubt and both EAE and MS manifest as a consequence of activation of myelin- reactive pathogenic T lymphocytes. Usually, T regulatory cells (Tregs), a subset of suppressive T lymphocytes, keep the myelin-specific pathogenic T cells in check and maintain peripheral tolerance. However, circumstances exist under which this control fails and autoimmunity transpires. To date much work has been done to demonstrate the suppressive function of Tregs. However, little is known regarding the development of Tregs and the circumstances under which they expand to counter autoimmunity. The long term objective of this proposal is to determine whether Tregs undergo selection and if they do, whether such selection is driven by the strength of T cell receptor (TCR)-ligand interactions. The hypothesis in this application postulates that Tregs undergo thymic selection and require rather high avidity for maturation. To test this hypothesis we propose to deliver altered peptides with degenerate TCR affinity for fetal presentation and test for fetal thymic Tregs selection and maturation and evaluate the consequences of such development on the peripheral expansion of Tregs in the offspring as well as their ability to modulate EAE. The SJL/J mouse expresses only the DM20 form of proteolipid protein (PLP) during fetal and neonatal life. DM20 is a mutant form of PLP missing the immunodominant PLP1 sequence corresponding to amino acid residues 139-151 of PLP. It has been shown that thymic negative selection against PLP1 is defective during the fetal/neonatal period. Immunoglobulins (Igs) can cross the maternal placenta and transfer from mother to fetus. Igs are also permissive for molecular grafting and expression of peptides within the heavy complementarily determining region-3 (CDR3). Herein, we propose to express PLP1 as well as PLP1-derived altered peptides on Igs and utilize the resulting Ig chimeras to deliver the peptides through the SJL/J maternal placenta and restore presentation during fetal life. Subsequently, we will evaluate the effect of such fetal presentation on Tregs selection, maturation, migration to the periphery and modulation of EAE.T regulatory cells (Tregs) represent a subset of suppressive cells that control peripheral tolerance and prevent the development of autoimmunity. Understanding how Tregs develop, mature, and carry out suppressive functions should impact the design of approaches to modulate autoimmunity. This proposal takes advantage of a unique peptide delivery system and a suitable mouse strain to investigate the development of Tregs. The study is highly significant and could impact the field of autoimmunity both at the level of basic science and clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057194-04
Application #
8048988
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2008-04-15
Project End
2013-04-30
Budget Start
2011-04-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2011
Total Cost
$307,520
Indirect Cost
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
Barik, Subhasis; Miller, Mindy; Cattin-Roy, Alexis et al. (2018) A distinct dendritic cell population arises in the thymus of IL-13R?1-sufficient but not IL-13R?1-deficient mice. Cell Immunol 331:130-136
Barik, Subhasis; Cattin-Roy, Alexis N; Miller, Mindy M et al. (2018) IL-4 and IL-13 Guide Early Thymic Progenitors To Mature toward Dendritic Cells. J Immunol 201:2947-2958
Barik, Subhasis; Ellis, Jason S; Cascio, Jason A et al. (2017) IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis. J Immunol 199:2236-2248
Barik, Subhasis; Miller, Mindy M; Cattin-Roy, Alexis N et al. (2017) IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage. J Immunol 199:2767-2776
Ukah, Tobechukwu K; Cattin-Roy, Alexis N; Chen, Weirong et al. (2017) On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes. J Immunol 199:894-902
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
Wan, Xiaoxiao; Guloglu, F Betul; VanMorlan, Amie M et al. (2012) Mechanisms underlying antigen-specific tolerance of stable and convertible Th17 cells during suppression of autoimmune diabetes. Diabetes 61:2054-65
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

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