title: Human CD8 transgene regulation of HLA recognition by murine T cells.
abstract: A series of human CD8 transgenic (hCD8 Tg) mice with differential expression in the thymus and periphery were produced to investigate CD8 coreceptor regulation of repertoire selection and T cell responses. Expression of hCD8 markedly enhanced responses to both HLA class I molecules and hybrid A2/Kb molecules providing functional evidence for a second interaction site, outside of the alpha 3 domain, which is essential for optimal coreceptor function. Peripheral T cell expression of hCD8 was sufficient to augment responsiveness to HLA class I, as hCD8 Tg mice which lacked thymic expression responded as well as mice expressing hCD8 in the thymus and periphery. Both murine CD8+ and CD4+ T cells expressing hCD8 transgenes exhibited markedly enhanced responses to foreign HLA class I, revealing the ability of T cell receptor repertoires selected on either murine class I or class II to recognize human class I major histocompatibility complex (MHC). In contrast to recognition of foreign class I, thymic expression of hCD8 transgenes was absolutely required to enhance recognition of antigenic peptide restricted by self-HLA class I. Thus, our studies revealed disparate requirements for CD8 coreceptor expression in the thymus for selection of a T cell repertoire responsive to foreign MHC and to antigenic peptides bound to self-MHC, providing a novel demonstration of positive selection that is dependent on human CD8.
authors.affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: LaFace
authors.forename: M
authors.initials: M
authors.lastname: Vestberg
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: R
authors.initials: R
authors.lastname: Srivastava
authors.forename: J
authors.initials: J
authors.lastname: DiSanto
authors.forename: N
authors.initials: N
authors.lastname: Flomenberg
authors.forename: S
authors.initials: S
authors.lastname: Brown
authors.forename: L A
authors.initials: LA
authors.lastname: Sherman
authors.forename: P A
authors.initials: PA
authors.lastname: Peterson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D016827:CD8 Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics; D006183:H-2 Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009975:Orthomyxoviridae / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013950:Thymus Gland / Q000378:metabolism; D019076:Transgenes; D014407:Tumor Cells, Cultured
chemical_list: D000956:Antigens, Viral; D016827:CD8 Antigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D005914:Globins