title: The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4.
abstract: Analysis of HLA class II transgenic mice has progressed in recent years from analysis of single chain HLA class II transgenes with expression of mixed mouse/human heterodimers to double transgenic mice expressing normal human heterodimers. Previous studies have used either HLA transgenic mice in which there is a species-matched interaction with CD4 or mice which lack this interaction. Since both systems are reported to generate HLA-restricted responses, the matter of the requirement for species-matched CD4 remains unclear. We have generated triple transgenic mice expressing three human transgenes, DRA, DRB, and CD4, and compared HLA-restricted responses to peptide between human-CD4+ (Hu-CD4+) and Hu-CD4- littermates. We saw no difference between Hu-CD4+ and Hu-CD4- groups, supporting the notion that for some responses at least the requirement for species-matched CD4 may not be absolute. Evidence for positive selection of mouse T cell receptors in HLA-DR transgenic mice came both from the acquisition of new, HLA-restricted responses to various peptides and from an increased frequency of T cells using the TCR V beta 4 gene segment. An important goal with respect to the analysis of function in HLA transgenic mice is the clarification of mechanisms which underpin the recognition of self-antigens in human autoimmune disease. As a first step towards 'humanized' disease models in HLA transgenic mice, we analyzed the responses of HLA-DR transgenic mice to the human MPB 139-154 peptide which has been implicated as an epitope recognized by T cells of multiple sclerosis patients. We obtained T cell responses to this epitope in transgenic mice but not in nontransgenic controls. This study suggests that HLA transgenic mice will be valuable in the analysis of HLA-restricted T cell epitopes implicated in human disease and possibly in the design of new disease models.
authors.affiliation: MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
authors.forename: D M
authors.initials: DM
authors.lastname: Altmann
authors.forename: D C
authors.initials: DC
authors.lastname: Douek
authors.forename: A J
authors.initials: AJ
authors.lastname: Frater
authors.forename: C M
authors.initials: CM
authors.lastname: Hetherington
authors.forename: H
authors.initials: H
authors.lastname: Inoko
authors.forename: J I
authors.initials: JI
authors.lastname: Elliott
mesh_terms: D000818:Animals; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007114:Immunization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D006684:HLA-DR Antigens; D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta