EXCEED THE SPACE PROVIDED The goal of this study is to gain an improved understanding of T cell recognition in murine experimental autoimmune encephalomyelitis (EAE) CD4+ T cells which recognize the N-terminal epitope of myelin basic protein (MBPI-11, core ofepitope, MBP1-9) associated with the MHC Class II molecule, I-A u, are the focus of our studies Our recent analyses in H-2 u mice indicate that the avidity ofMBP1-9 I-A u specific T cells for cognate ligand correlates with encephalitogenicity We have also carried out a detailed analysis of the properties of two Tcell receptors (TCRs, '1934 4' and '172 10') derived from MBP1-9 I-A u specific T cells for which TCR transgenic (tg) mice are available These studies show a correlation between TCR affinity and conformational flexibility ('plasticity9 They also suggest that TCR affinity/plasticity might correlate with the susceptibility of the corresponding TCR tg mice to spontaneous disease However, other factors may contribute to, or be solely responsible for, differences in spontaneous disease susceptibility and this possibility will be investigated further here Our hypotheses are First, that T cells expressing TCRs with higher affinity for antigen are more readily triggered than ceils bearing lower aff'mity TCRs Second, that autoreactive, pathogenic T cells express TCRs with distinct kinetics and thermodynamics for ligand binding when compared with TCRs bome by T cells of lower pathogenic potential Third, that it may be possible to combine mutagenesis and functional studies to identify regions of particular TCRs that are responsible for high affinity and/or plastic recognition Our specific alms are 1) to analyze the properties of 172 10 and 1934 4 TCR transgenic T cells, 2) to analyze the affinities, plasticities and cross-reactivities of the TCRs expressed by responding T cells in immunized mice and to con'elate these properties with pathogenicity, 3) to characterize in molecular detail the TCR-pMHC interactions for a subset of the TCRs which have different affinities, plasticities and cross-reactivities These studies should lead to an improved understanding of the factors that lead to the activation of autoreactive T cells and have general relevance to T cell recognition PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042949-06
Application #
6827857
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Esch, Thomas R
Project Start
1998-07-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
6
Fiscal Year
2005
Total Cost
$312,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Pastor, Silvia; Minguela, Alfredo; Mi, Wentao et al. (2009) Autoantigen immunization at different sites reveals a role for anti-inflammatory effects of IFN-gamma in regulating susceptibility to experimental autoimmune encephalomyelitis. J Immunol 182:5268-75
Mi, Wentao; Wanjie, Sylvia; Lo, Su-Tang et al. (2008) Targeting the neonatal fc receptor for antigen delivery using engineered fc fragments. J Immunol 181:7550-61
Minguela, Alfredo; Pastor, Silvia; Mi, Wentao et al. (2007) Feedback regulation of murine autoimmunity via dominant anti-inflammatory effects of interferon gamma. J Immunol 178:134-44
Pastor, Silvia; Vaccaro, Carlos G; Minguela, Alfredo et al. (2006) Analyses of TCR clustering at the T cell-antigen-presenting cell interface and its impact on the activation of naive CD4+ T cells. Int Immunol 18:1615-25
Huang, Jason C; Ober, Raimund J; Ward, E Sally (2005) The central residues of a T cell receptor sequence motif are key determinants of autoantigen recognition in murine experimental autoimmune encephalomyelitis. Eur J Immunol 35:299-304
Huang, Jason C; Vestberg, Mikael; Minguela, Alfredo et al. (2004) Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide-MHC multimers. Int Immunol 16:283-93
Huang, Jason C; Han, Mei; Minguela, Alfredo et al. (2003) T cell recognition of distinct peptide:I-Au conformers in murine experimental autoimmune encephalomyelitis. J Immunol 171:2467-77
He, Xiao-lin; Radu, Caius; Sidney, John et al. (2002) Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immunodominant epitope of MBP complexed with I-Au. Immunity 17:83-94
Deng, Caishu; Minguela, Alfredo; Hussain, Rehana Z et al. (2002) Expression of the tyrosine phosphatase SRC homology 2 domain-containing protein tyrosine phosphatase 1 determines T cell activation threshold and severity of experimental autoimmune encephalomyelitis. J Immunol 168:4511-8
Qadri, A; Ward, E S (2001) Activation of a T cell hybridoma by an alloligand results in differential effects on IL-2 secretion and activation-induced cell death. Eur J Immunol 31:3825-32

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