Nonclassical class I (Ibeta) genes comprise most of the class I genes of mouse and man. Only recently has it become apparent that at least some of these molecules play important roles in the immune response. We propose to focus our studies on the murine class Ibeta molecule, Qa-1. This antigen is polymorphic, expressed ubiquitously, and known to present a synthetic polymer to gammadelta T cells as well as interact with a peptide deprived from Hsp-65 from M. bovis. Conserved residues in the F pocket of the Qa-1 peptide binding groove differ from those of the class Ia consensus. Therefore, our studies will focus on peptides that are recognized by Qa-1 specific cytotoxic T lymphocytes (CTL) with the aim of increasing our understanding of antigen processing and presentation in the class I pathway. One such peptide is controlled by a gene(s) termed Qdm (Qa-1 determinant modifier). We have identified the Qdm-peptide as being encoded by class Ia D-end alleles, except for Dk, and synthetic peptides derived from these molecules are presented by Qa1b to our Qa1b anti-Qa-1b (Qdm- dependent) CTL clones. We will characterize which peptide is identical to the natural peptide eluted from Qa-1b lymphoblasts, and determine the residues in the peptide that are important for binding to Qa-1b. The Qdm- peptide is also eluted from Qa-1a lymphoblasts. Therefore, we will generate Qdm-dependent Qa-1b anti-Qa-1a CTL clones and determine if they recognize the same peptide as the """"""""a anti-b"""""""" clones, as well as whether the peptide binds these two Qa-1 alleles in the same manner. The Qdm-negative (Dk) peptide will also be characterized since Qdm-dependent CTL can be generated in H-2k strains. The CDR3 region of the Vbeta and Valpha T cell receptors from this unique panel of alloreactive and peptide-specific CTL clones will be sequenced. As a result of these experiments we will define the first peptide(s) that binds to Qa-1 and is recognized by specific CTL. In addition, the availability fee these unique peptide-specific alloreactive CTL will allow us to determine how the same peptide is presented by two different alleles of an alloantigen as well as compare how peptide vs. alloantigen influence T cell receptor recognition. The Fee peptide is not expressed on RYA-S (Tap-2 defective) cells or lymphoblasts from Tap-1knockout animals. Surprisingly, the peptide is contained in the signal peptide of D-end antigens, and contrasts with other reports where leader peptides are expressed on mambrane class I molecules in cells lacking transporter function. Therefore, we will use the Qdm- peptide as a probe to examine aspects of antigen processing of leader- derived epitopes. This will provide novel information not only on the processing of these antigens, but also on the traffic of leader peptides within the cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI034930-01A1
Application #
2070208
Study Section
Experimental Immunology Study Section (EI)
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Su, Jie; Berg, Rance E; Murray, Sean et al. (2005) Thymus-dependent memory phenotype CD8 T cells in naive B6.H-2Kb-/-Db-/- animals mediate an antigen-specific response against Listeria monocytogenes. J Immunol 175:6450-7
Kurepa, Zoran; Su, Jie; Forman, James (2003) Memory phenotype of CD8+ T cells in MHC class Ia-deficient mice. J Immunol 170:5414-20
Bai, A; Aldrich, C J; Forman, J (2000) Factors controlling the trafficking and processing of a leader-derived peptide presented by Qa-1. J Immunol 165:7025-34
Seaman, M S; Perarnau, B; Lindahl, K F et al. (1999) Response to Listeria monocytogenes in mice lacking MHC class Ia molecules. J Immunol 162:5429-36
Kronenberg, M; Brossay, L; Kurepa, Z et al. (1999) Conserved lipid and peptide presentation functions of nonclassical class I molecules. Immunol Today 20:515-21
Kurepa, Z; Hasemann, C A; Forman, J (1998) Qa-1b binds conserved class I leader peptides derived from several mammalian species. J Exp Med 188:973-8
Bai, A; Broen, J; Forman, J (1998) The pathway for processing leader-derived peptides that regulate the maturation and expression of Qa-1b. Immunity 9:413-21
Speiser, D E; Bachmann, M F; Soloski, M J et al. (1998) Alloreactive cytotoxic T cells recognize minor transplantation antigens presented by major histocompatibility complex class Ib molecules. Transplantation 66:646-50
Bai, A; Forman, J (1997) The effect of the proteasome inhibitor lactacystin on the presentation of transporter associated with antigen processing (TAP)-dependent and TAP-independent peptide epitopes by class I molecules. J Immunol 159:2139-46
Kurepa, Z; Forman, J (1997) Peptide binding to the class Ib molecule, Qa-1b. J Immunol 158:3244-51

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