Title

Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions.

Document Type

Article

Publication Date

2000

Keywords

Cell-Lineage, Clone-Cells, CD4-Positive-T-Lymphocytes, CD8-Positive-T-Lymphocytes, Diabetes-Mellitus-Insulin-Dependent, Female, Gene-Expression-Regulation, Histocompatibility-Antigens-Class-I, Islets-of-Langerhans, Mice, Mice-Inbred-NOD, Mice-SCID, Mice-Transgenic, Receptors-Antigen-T-Cell-alpha-beta, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes-Helper-Inducer, Transgenes

JAX Source

J Immunol 2000 Apr; 164(7):3913-8.

Grant

DK46266/DK/NIDDK, DK51090/DK/NIDDK, AI41469/AI/NIAID

Abstract

Previous work has indicated that an important component for the initiation of autoimmune insulin-dependent diabetes mellitus (IDDM) in the NOD mouse model entails MHC class I-restricted CD8 T cell responses against pancreatic beta cell Ags. However, unless previously activated in vitro, such CD8 T cells have previously been thought to require helper functions provided by MHC class II-restricted CD4 T cells to exert their full diabetogenic effects. In this study, we show that IDDM development is greatly accelerated in a stock of NOD mice expressing TCR transgenes derived from a MHC class I-restricted CD8 T cell clone (designated AI4) previously found to contribute to the earliest preclinical stages of pancreatic beta cell destruction. Importantly, these TCR transgenic NOD mice (designated NOD.AI4alphabeta Tg) continued to develop IDDM at a greatly accelerated rate when residual CD4 helper T cells were eliminated by introduction of the scid mutation or a functionally inactivated CD4 allele. In a previously described stock of NOD mice expressing TCR transgenes derived from another MHC class I-restricted beta cell autoreactive T cell clone, IDDM development was retarded by elimination of residual CD4 T cells. Hence, there is variability in the helper dependence of CD8 T cells contributing to the development of autoimmune IDDM. The A14 clonotype represents the first CD8 T cell with a demonstrated ability to progress from a naive to functionally activated state and rapidly mediate autoimmune IDDM development in the complete absence of CD4 T cell helper functions.