Autoreactive Diabetogenic T-Cells in NOD Mice Can Efficiently Expand From a Greatly Reduced Precursor Pool
- David V. Serreze1,
- Ellis A. Johnson1,
- Harold D. Chapman1,
- Robert T. Graser1,
- Michele P. Marron1,
- Teresa P. DiLorenzo2,
- Pablo Silveira1,
- Yoshitaka Yoshimura3,
- Stanley G. Nathenson2 and
- Sebastian Joyce3
- 1The Jackson Laboratory, Bar Harbor, Maine
- 2Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York
- 3Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
A broad repertoire of pancreatic β-cell autoreactive T-cells normally contributes to the development of type 1 diabetes in NOD mice. However, it has been unknown if a large reduction in the precursor pool from which autoreactive T-cells are drawn would inhibit the development of type 1 diabetes. To address this issue, we reduced the precursor frequency of autoreactive T-cells in NOD mice through allelic exclusion induced by transgenic expression of an H2-Db class I−restricted T-cell receptor (TCR) specific for a pathologically irrelevant lymphocytic choriomeningitis virus (LCMV) peptide. TCR allelic exclusion greatly reduced the pool of T-cells from which diabetogenic effectors could be derived in these NOD.LCMV TCR Tg mice. Surprisingly, this did not impair their type 1 diabetes susceptibility. Furthermore, a diabetogenic CD8 T-cell population that is prevalent in standard NOD mice was present at essentially equivalent levels in pancreatic islets of NOD.LCMV TCR Tg mice. Other data indicated that the antigenic specificity of these CD8 T-cells is primarily the function of a shared TCR-α chain. Although the percentage of TCR transgenic T-cells decreased in NOD versus B6,D2 control mice, much higher total numbers of both the TCR transgenic and the nontransgenic T-cells accumulated in the NOD strain. This transgenic T-cell accumulation in the absence of the cognate peptide indicated that the NOD genetic background preferentially promotes a highly efficient antigen-independent T-cell expansion. This might allow diabetogenic T-cells in NOD mice to undergo an efficient expansion before encountering antigen, which would represent an important and previously unconsidered aspect of pathogenesis.
Address correspondence and reprint requests to Dr. David V. Serreze, Staff Scientist, The Jackson Laboratory, Bar Harbor, ME 04609. E-mail:.
Received for publication 18 December 2000 and accepted in revised form 31 May 2001.
APC, antigen-presenting cell; FACS, fluorescence-activated cell sorter; FITC, fluorescein isothiocyanate; IL, interleukin; LCMV, lymphocytic choriomeningitis virus; MHC, major histocompatibility complex; PBL, peripheral blood leukocyte; PCR, polymerase chain reaction; PE, phycoethrin; TCR, T-cell receptor; Tg, transgenic.