C57BL/6 mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) develop acute and chronic demyelinating encephalomyelitis and thereby serve as a useful model for the human disease multiple sclerosis. Demyelination is largely immune-mediated and reflects a balance between pro-inflammatory factors necessary for virus clearance and anti-inflammatory factors critical for limiting bystander tissue damage. Virus clearance requires robust virus-specific CD8 and CD4 T cell responses. In the previous funding period, we showed that optimization of the CD8 T cell response, by mutating a subdominant CD8 T cell epitope, enhanced virus clearance. However, disease course was not changed. We showed that this was due to a pathogenic CD4 T cell response directed at the immunodominant M133 epitope. Only naive M133-specific CD4 T cells were pathogenic because we also showed that memory virus-specific CD4 T cells were protective. We also identified a potent regulatory T cell (Treg, Foxp3+) response directed against the M133 epitope, adding another layer of complexity to the balance between pro and anti-inflammatory factors. To probe these interactions in more detail, we developed mice that were retrogenic or transgenic for expression of an M133-specific T cell receptor. The central objective of this proposal is to investigate in more detail the balance of these immune factors, as delineated in the following specific aims.
In Aim 1, factors in M133-specific CD4 T cells that result in pathogenicity (naive T cells) or protection (memory T cells) will be investigated, using our newly developed M133-specific retrogenic and transgenic TCR mice. Adoptive transfer experiments and targeted and genome-wide gene expression approaches will be used in this aim.
In Aim 2, the role of M133-specific Tregs in pathogenesis in JHMV-infected mice will be investigated, also taking advantage of the M133- specific TCR transgenic mice. As part of this aim, we will assess whether virus-specific Tregs are more suppressive than bulk Treg populations and whether Tregs enter the memory T cell pool. We will also determine whether pathogen-specific Tregs require expression of a second TCR ? chain, recognizing a self epitope, for suppressive function.

Public Health Relevance

Demyelination, which occurs after many viral infections of the central nervous system, is largely mediated by the host immune response during virus clearance. This application is directed at understanding aspects of the anti-virus immune response that are protective or pathogenic, with focus on the anti-inflammatory component of the immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036592-15
Application #
8423310
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
1997-09-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$317,891
Indirect Cost
$106,797
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Trujillo, Jonathan A; Gras, Stephanie; Twist, Kelly-Anne et al. (2014) Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes. J Immunol 192:5245-56
Channappanavar, Rudragouda; Zhao, Jincun; Perlman, Stanley (2014) T cell-mediated immune response to respiratory coronaviruses. Immunol Res 59:118-28
Zhao, Jingxian; Zhao, Jincun; Perlman, Stanley (2014) Virus-specific regulatory T cells ameliorate encephalitis by repressing effector T cell functions from priming to effector stages. PLoS Pathog 10:e1004279
Lin, Shing-Yen; Liu, Chia-Ling; Chang, Yu-Ming et al. (2014) Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target. J Med Chem 57:2247-57
Trujillo, Jonathan A; Croft, Nathan P; Dudek, Nadine L et al. (2014) The cellular redox environment alters antigen presentation. J Biol Chem 289:27979-91
Chen, I-Jung; Yuann, Jeu-Ming P; Chang, Yu-Ming et al. (2013) Crystal structure-based exploration of the important role of Arg106 in the RNA-binding domain of human coronavirus OC43 nucleocapsid protein. Biochim Biophys Acta 1834:1054-62
Zhao, Jingxian; Fett, Craig; Pewe, Lecia et al. (2013) Development of transgenic mice expressing a coronavirus-specific public CD4 T cell receptor. J Immunol Methods 396:56-64
Zhao, Jingxian; Zhao, Jincun; Fett, Craig et al. (2011) IFN-?- and IL-10-expressing virus epitope-specific Foxp3(+) T reg cells in the central nervous system during encephalomyelitis. J Exp Med 208:1571-7
Trandem, Kathryn; Jin, Qiushuang; Weiss, Kayla A et al. (2011) Virally expressed interleukin-10 ameliorates acute encephalomyelitis and chronic demyelination in coronavirus-infected mice. J Virol 85:6822-31
Williamson, Nicholas A; Reilly, Charles; Tan, Chor-Teck et al. (2011) A novel strategy for the targeted analysis of protein and peptide metabolites. Proteomics 11:183-92

Showing the most recent 10 out of 38 publications