T-cell receptor transgenic response to an endogenous polymorphic autoantigen determines susceptibility to diabetes.
We have produced a T-cell receptor (TCR) transgenic NOD mouse, 6.9TCR/NOD, in which the expression of both diabetogenic T-cells and naturally occurring autoantigen were simultaneously controlled. The parent T-cell clone, BDC-6.9, and T-cells from 6.9TCR/NOD mice recognize a currently unidentified antigen present in NOD but not in BALB/c islet cells. A gene that codes for the antigen, or a protein that regulates the antigen, was previously mapped to a locus on chromosome 6. We have developed transgenic mice bearing the TCR alpha- and beta-chains from the BDC-6.9 T-cell clone on a NOD congenic background in which the antigen locus on chromosome 6 of the NOD mouse is replaced by a segment from BALB/c. These NOD.C6 congenic mice lack the NOD islet cell antigen to which the BDC-6.9 T-cell clone responds. Diabetes in both male and female 6.9TCR/NOD mice is dramatically accelerated, but in 6.9TCR/NOD.C6 mice lacking the NOD islet cell autoantigen, we have not observed diabetes for up to 1 year of age. Thus, the generation of 6.9TCR transgenic mice provides a model of autoimmune diabetes whereby controlled expression of an endogenous polymorphic autoantigen effectively determines disease development.
Pauza
Mary E
ME
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
Dobbs
Cathleen M
CM
He
Jing
J
Patterson
Tricia
T
Wagner
Steven
S
Anobile
Brian S
BS
Bradley
Brenda J
BJ
Lo
David
D
Haskins
Kathryn
K
D000818:Animals; D001324:Autoantigens / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002874:Chromosome Mapping; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000235:genetics* / Q000276:immunology; D004198:Disease Susceptibility; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000235:genetics; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D017931:DNA Primers; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell