This proposal requests support for the continued investigation of the Q and T region class Ib genes and their products. These major histocompatibility complex antigens are similar in structure to the classical class I molecules; however, biological functions have yet to be established clearly. Our efforts focus on the structure/function of the Qa-1, TL, and Qa-2 molecules and the molecular regulation of th T18 and T23 genes. Direct evidence for mechanisms through which the classical class I molecules restrict recognition of antigen by T cells came from the proof that they bound endogenous peptides and the determination of amino acid sequences for these prptides. It is suspected but not proven that the Q and T region encoded molecules similarly bind peptides derived from self and foreign antigen.
Our first aim i s to isolate the Qa-1, TL, and Qa-2 molecules from cell lines and determine the amino acid sequence of peptides released from their antigen binding clefts. This line of investigation will 1) define what types of antigens can be presented by these class I molecules; 2) determine whether their functions are specialized or generalized like classical class I antigens; and 30 provide a foundation for more detailed structural analyses. We previously determined that the T23 gene encoded the Qa-1b molecule and our second aim addresses distinctive features of this protein. We will isolate the characterize an H-2S region gene designated Qsm responsible for a modification of Qa-1 that leads to alternative cell surface forma. We also will address mechanisms responsible for the rapid turnover of Qa-1 and dependence upon oligosaccharide for cell surface expression.
Our third aim i s to define regulatory elements responsible for the control of expression of the T18 and T23 genes. T18, which encodes TL, has a very restricted tissue distribution, while T23 which encodes Qa-1 has a more or less ubiquitous level of expression. Neither of these genes have in their 5' regions the consensus regulatory elements of classical class I genes. Thus, a delineation of the promoter/enhancer regions and transcription factors that bind to these elements will provide new information regarding tissue specific versus constitutive expression of class I genes. We have found that T18 has an unusual promoter and will dissect it further as part of this aim. We are confident that these proposed studies will answer pertinent and fundamental questions about the immune function of the Q and T region molecules and mechanisms that regulate their expression and further our understanding of the biological roles of class I molecules in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI017897-12A1
Application #
3127503
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1981-04-01
Project End
1996-06-30
Budget Start
1993-09-30
Budget End
1994-06-30
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Doyle, C Kuyler; Cook, Richard G; Rich, Robert R et al. (2003) Cotton rat Sihi-M3 is a minimally oligomorphic Mhc I-b molecule that binds the chemotactic peptide fMLF under stringent conditions. Evidence that positive selection drives inter-species diversity of residues interacting with the termini of short peptides. Immunogenetics 55:389-94
Davis, Beckley K; Cook, Richard G; Rich, Robert R et al. (2002) Hyperconservation of the putative antigen recognition site of the MHC class I-b molecule TL in the subfamily Murinae: evidence that thymus leukemia antigen is an ancient mammalian gene. J Immunol 169:6890-9
Wolf, P R; Cook, R G (1995) The class I-b molecule Qa-1 forms heterodimers with H-2Ld and a novel 50-kD glycoprotein encoded centromeric to I-E beta. J Exp Med 181:657-68
Wang, I M; Mehta, V; Cook, R G (1993) Regulation of TL antigen expression. Analysis of the T18d promoter region and responses to IFN-gamma. J Immunol 151:2646-57
Cook, R G; Leone, B; Leone, J W et al. (1992) Characterization of T cell proliferative responses induced by anti-Qa-2 monoclonal antibodies. Cell Immunol 144:367-81
Widacki, S M; Mehta, V; Flaherty, L et al. (1990) Biochemical differences in Qa-2 antigens expressed by Qa-2+,6+ and Qa-2+,6- strains. Evidence for differential expression of the Q7 and Q9 genes. Mol Immunol 27:559-70
Dolby, N; Mehta, V; Cook, R G (1990) Regulation of expression of TL genes of the mouse Mhc. Immunogenetics 32:380-8
Wolf, P R; Cook, R G (1990) The TL region gene 37 encodes a Qa-1 antigen. J Exp Med 172:1795-804
Pollack, M S; Hayes, A; Mooney, S et al. (1988) The detection of conventional class I and class II I-E homologue major histocompatibility complex molecules on feline cells. Vet Immunol Immunopathol 19:79-91
Davis, J E; Cook, R G; Van, M et al. (1988) Polymorphic Bgl II restriction sites of DR alpha demarcate a novel HLA-DR1 antigen. Immunogenetics 28:171-81

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