The T cell receptor (TCR) is critical in defining the specificity component of T cell function. In turn, T cell-specific responsiveness is important in maintaining immune surveillance and establishing immunologic memory against invading pathogens. Unfortunately, this defensive mechanism may also direct itself against self antigens and may result in T cell- mediated autoimmune disease. One long term goal of this study is to gain better understanding of TCR-specific reactivity, particularly as it pertains to autoreactivity. We wish to pursue this using the T cell mediated autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). EAE can be actively induced by immunization with components of the myelin sheath such as myelin basic protein (BP) or proteolipid protein (PLP) and can also be induced by passive transfer of T cells specific for encephalitogenic peptides of BP or PLP. TCR V gene utilization in EAE- inducing, BP-specific T cells has been analyzed to different extents in rats and mice and appears to be restricted. In the Lewis rat model of EAE, T cells specific for BP72-89 demonstrate dominant V-beta-8.2 expression in association with a CDR3 motif, perhaps identifying residues important in contacting MHC-bound peptide. The involvement of these and other V-beta- 8.2 CDR residues in peptide/MHC recognition will be directly tested in this proposal. In addition, because the characterization of V-alpha expression in rat EAE has been relatively limited, the role of V-alpha in EAE will be further investigated here as well. Biased V gene usage in EAE has led to several experimental therapies which target the surface-expressed TCR. The EAE-associated V-beta CDR3, formed by junctional regions between V-beta and D-beta, as well as D-beta and J- beta segments, may not only play a significant role in antigen/MHC recognition, but may constitute a unique marker for encephalitogenic T cells. The generation of monoclonal antibodies which include recognition of this marker would be extremely useful for detecting encephalitogenic T cells within a heterogeneous population prior to disease onset. In addition, these monoclonal antibodies may have potential therapeutic value.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29NS035207-04S1
Application #
6062297
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1996-04-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Neurology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Buenafe, Abigail C; Tsaknaridis, Laura; Spencer, Leslie et al. (2004) Specificity of regulatory CD4+CD25+ T cells for self-T cell receptor determinants. J Neurosci Res 76:129-40
McMahan, Rachel H; Watson, Lisa; Meza-Romero, Roberto et al. (2003) Production, characterization, and immunogenicity of a soluble rat single chain T cell receptor specific for an encephalitogenic peptide. J Biol Chem 278:30961-70
Buenafe, A C; Tsu, R C; McMahan, R et al. (2001) Rat RT1.B-transfected fibroblast lines process and present myelin antigens and activate T cells to induce experimental autoimmune encephalomyelitis. J Neuroimmunol 112:106-14
Buenafe, A C; Offner, H; Machnicki, M et al. (1998) EAE TCR motifs and antigen recognition in myelin basic protein-induced anterior uveitis in Lewis rats. J Immunol 161:2052-9
Buenafe, A C; Tsu, R C; Bebo Jr, B et al. (1997) A TCR V alpha CDR3-specific motif associated with Lewis rat autoimmune encephalomyelitis and basic protein-specific T cell clones. J Immunol 158:5472-83