Development and Function of Diabetogenic T-cells in B-cell–Deficient Nonobese Diabetic Mice
- 1Program in Developmental Biology, the Hospital for Sick Children Research Institute
- 2Departments of Surgery and
- 3Immunology and the
- 4Institute of Medical Science, University of Toronto, Ontario, Canada
- 5Jackson Laboratory, Bar Harbor, Maine
Abstract
Insulin-dependent diabetes (type 1 diabetes) in the NOD mouse is a T-cell–mediated autoimmune disease. However, B-cells may also play a critical role in disease pathogenesis, as genetically B-cell–deficient NOD mice (NOD.μMT) have been shown to be protected from type 1 diabetes and to display reduced responses to certain islet autoantigens. To examine the requirements for B-cells in the development of type 1 diabetes, we generated a B-cell–naive T-cell repertoire by transplantation of NOD fetal thymuses (FTs) into NOD.scid recipients. Surprisingly, these FT-derived NOD T-cells were diabetogenic in 36% of NOD.scid recipients, despite the absence of B-cells. In addition, T-cells isolated from NOD.μMT mice were diabetogenic in 22% of NOD.scid recipients. Together, these results indicate that B-cells are not an absolute requirement for the generation or effector function of an islet-reactive T-cell repertoire in NOD mice. We suggest that conditions favoring rapid lymphocyte expansion can reveal autoreactive T-cell activity and precipitate disease in genetically susceptible individuals.
- Ab, antibody
- Ag, antigen
- APC, Ag-presenting cell
- BSA, bovine serum albumin
- Cμ2A, Ig Cμ
- 3′-primer
- DC; dendritic cell
- FACS, fluorescence-activated cell sorter
- FITC, fluorescein isothiocyanate
- FT, fetal thymus
- Igh, Ig heavy chain
- KLH, keyhole limpet hemocyanin
- LN, lymph node
- mAb, monoclonal antibody
- MHC, major histocompatibility complex
- μMT, Igμ constant transmembrane region
- PBL, peripheral blood lymphocyte
- PBS, phosphate-buffered saline
- PI, propidium iodide
- RT-PCR, reverse transcriptase–polymerase chain reaction
- VHALL, Ig Vh 5′-primer
Footnotes
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Address correspondence and reprint requests to Dr. Jayne Danska, The Hospital for Sick Children Research Institute, 555 University Ave., Toronto, Ontario, Canada, M5G 1X8. E-mail: danska{at}sickkids.on.ca.
Received for publication 28 August 2000 and accepted in revised form 22 December 2000.
