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

SUITIH1 al'yAnalysis 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 V34 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.

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

“…Previously described HLA-DR1-transgenic mice (designated C57BL/6J 0-0 HLA-DR1) carrying full-length genomic constructs for HLA-DRA1*0101 and HLA-DRB1*0101 (26) were crossed for more than 6 generations to C57BL/6 A b -null mice (27) and genotyped by polymerase chain reaction for the presence of the HLA transgenes. This newly derived strain of DR1-transgenic mice lacked both human CD4 and endogenous mouse class II MHC molecules and was characterized by 1) a normal distribution of DR1ϩ lymphoid cell types in the spleen, 2) the expression of DR1 molecules on professional APCs, but not on CD4 or CD8 T cells, 3) a normal distribution of T cell receptor (TCR) V ␤ family expression among spleen cells, and 4) the susceptibility to CIA (Von Delwig A, et al: unpublished observations).…”

The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent ofStreptococcus pyogenes

“…Gated events (20,000) were counted for each sample. Animals C57BL/10.DQ8 transgenic mice carrying genomic constructs for DQA1*0301 and DQB*0302 and FVB/N.DR1 transgenic mice carrying genomic constructs for DRA1*0101 and DRB1*0101 have been previously described (8,9). For in vitro comparison of responsiveness to SMEZ, C57/BL10.DQ8 and FVB/N.DR1 transgenic mice both were used on a matched syngeneic (C57BL/10 ϫ FVB/N)F 1 background.…”

A Single TCRα-Chain with Dominant Peptide Recognition in the Allorestricted HER2/neu-Specific T Cell Repertoire

“…However, the outcome of the first trial (1) showed limited antimelanoma reactivity when compared with the application of tumor-infiltrating lymphocytes potentially because of the intermediate avidity of the TCRs used for transfer. TCRs with higher avidity for a tumor-associated self-Ag might be rarely isolated from autologous T cells, but rather be selected from T cells that recognize their target peptide in the context of a foreign MHC molecule or recognize allogeneic or xenogeneic peptides (3)(4)(5)(6). In fact, in the second clinical trial (2) two TCRs with specificity for MART1 and GP100 exhibiting higher avidity were transduced into PBMCs.…”