The """"""""superantigens"""""""" are a class of antigen that does not obey the normal rules of MHC-restricted antigen recognition. Superantigens stimulate a large proportion of T cells through a specific interaction with the beta-chain of the T cell receptor (TCR). Thus an individual superantigen such as Mis-1 or staphylococcal enterotoxin A, when presented by MHC class II, stimulates T cells bearing specific V-beta-regions. This project aims to analyze the affinity and structure of the interaction between the TCR beta-chain and the superantigen: class II complex. The mouse mammary tumor virus (MMTV) gene products that appear to be the endogenous superantigens such as Mls will also be investigated. A secreted form of the TCR beta-chain has recently been used to demonstrate that the beta-chain is sufficient to mediate recognition of a superantigen: class II complex. The affinity and rate constants for the reaction of various V-betas with superantigens will be determined. This will allow a minimal estimate of the affinity required for a beta-chain to undergo thymic deletion or peripheral activation. This information will be extremely important in understanding the basis of tolerance induction by negative selection in the thymus. The unusual structure of V-beta3 may be related to its reactivity with a wide range of superantigens. This V-beta will be mutated to investigate the importance of these unusual structural features on superantigenreactivity and on the affinity for ligand. Comparatively little is known about the MMTV proteins that act as superantigens. They appear to be a product of an open reading frame in the proviral 3' long terminal repeat. These gene products will be investigated as to their structure and function. The genes will be expressed and the protein purified to use in in vitro studies. It will be used to determine the interaction (if it exists) with class II and V-beta. The site on the superantigen involved in these interactions will be determined. Fragments of superantigen proteins will be used to determine the region of both bacterial and endogenous superantigens that interacts with the V-beta. Fragments of the MMTV protein will be used in similar studies to investigate binding to class II. The effect on superantigen-binding of defined structural mutants of class II molecules will be investigated. The crystal structure of an endogenous superantigen complexed to class II will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM046134-03
Application #
2183671
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1992-02-01
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1996-01-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Alam, S Munir; Gascoigne, Nicholas R J (2003) Binding kinetics of superantigen with TCR and MHC class II. Methods Mol Biol 214:65-85
Redpath, S; Ghazal, P; Gascoigne, N R (2001) Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol 9:86-92
McGuire, M V; Suthipinijtham, P; Gascoigne, N R (2001) The mouse Supt16h/Fact140 gene, encoding part of the FACT chromatin transcription complex, maps close to Tcra and is highly expressed in thymus. Mamm Genome 12:664-7
Gascoigne, N R; Alam, S M; Lin, C M et al. (2000) T cell receptor binding kinetics and special role of Valpha in T cell development and activation. Immunol Res 21:225-31
Redpath, S; Alam, S M; Lin, C M et al. (1999) Cutting edge: trimolecular interaction of TCR with MHC class II and bacterial superantigen shows a similar affinity to MHC:peptide ligands. J Immunol 163:6-10
Redpath, S; Angulo, A; Gascoigne, N R et al. (1999) Murine cytomegalovirus infection down-regulates MHC class II expression on macrophages by induction of IL-10. J Immunol 162:6701-7
Ghoshroy, S; Freedman, K; Lartey, R et al. (1998) Inhibition of plant viral systemic infection by non-toxic concentrations of cadmium. Plant J 13:591-602
Sheng, J; Lartey, R; Ghoshroy, S et al. (1998) An Arabidopsis thaliana mutant with virus-inducible phenotype. Virology 249:119-28
Lartey, R T; Ghoshroy, S; Citovsky, V (1998) Identification of an Arabidopsis thaliana mutation (vsm1) that restricts systemic movement of tobamoviruses. Mol Plant Microbe Interact 11:706-9
Wung, J L; Gascoigne, N R (1997) Selection of phage-displayed superantigen by binding to cell-surface MHC class II. J Immunol Methods 204:33-41

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