Selection of Aberrant Class II Restricted CD8+ T Cells in NOD Mice Expressing a Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgene

• Published in: Autoimmunity (Chur, Switzerland) Switzerland), 2004-12, Vol.37 (8), p.555-567
• Main Authors: Ranheim, Erik A., Tarbell, Kristin V., Krogsgaard, Michelle, Mallet-Designe, Valérie, Teyton, Luc, McDevitt, Hugh O., Weissman, Irving L.
• Format: Article
• Language: English
• Subjects: Animals; Autoantigens - genetics; Autoantigens - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cellular differentiation; Clonal Deletion - immunology; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; General aspects; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - immunology; Histocompatibility Antigens Class II - immunology; Immunopathology; Medical sciences; MHC; Mice; Mice, Inbred NOD; Mice, Transgenic; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; T cell receptors; Thymus
• ISSN: 0891-6934; 1607-842X
• DOI: 10.1080/08916930400020545

We previously described the generation of non-obese diabetic (NOD) mice expressing a transgenic T cell receptor (TCR) specific for peptide epitope 286-300 of the diabetes related self antigen, glutamic acid decarboxylase (GAD)65 in the context of I-Ag7 class II MHC, that are paradoxically protected from diabetes. In this report, we examine the atypical CD8+ cells in these mice. Unlike typical class II restricted TCR transgenic mice, GAD286 mice have normal numbers of CD8+ cells, half of which express high levels of the transgenic TCR. These MHC mismatched CD8+ cells persist in the periphery and proliferate to GAD286-300 peptide in vitro and in vivo in a class II restricted fashion. Interestingly, the CD8+ tetramer− T cells that are expressing endogenous TCR can delay diabetes induction in a transfer model, as we previously showed for CD4+ tetramer+ T cells in these mice. The MHC mismatched CD8+ cells appear to be positively selected in an atypical fashion, in that they do not upregulate CD69 or reexpress CD44, and they escape negative selection. We find that production of these CD8+ cells is not dependent on NOD thymus or high affinity of the TCR, but is dependent on the atypical TCR transgenic thymic environment.