TNF Receptor 1-Dependent β Cell Toxicity as an Effector Pathway in Autoimmune Diabetes

Author:

Kägi David1,Ho Alexandra1,Odermatt Bernhard2,Zakarian Arsen1,Ohashi Pamela S.1,Mak Tak W.1

Affiliation:

1. *Ontario Cancer Institute/Amgen Institute, Toronto, Ontario, Canada; and

2. †Department of Pathology, University of Zürich, Zürich, Switzerland

Abstract

Abstract Autoimmune diabetes is characterized by a chronic progressive inflammatory autoimmune reaction that ultimately causes the selective elimination of pancreatic β cells. To address the question of whether the cell death-inducing cytokines TNF and lymphotoxin α are involved in this process, we generated nonobese diabetic (NOD) mice that are deficient for TNF receptor 1 (TNFR1 or TNFRp55). Insulitis developed in these mice similarly to that in normal control NOD mice, but progression to diabetes was completely abrogated. Since this was probably due to the complex immunomodulatory effects of TNF and lymphotoxin α signaled via TNFR1 on lymphohemopoietic cells, adoptive transfer experiments with spleen cells from diabetic NOD mice were conducted. It was found that the absence of TNFR1 in recipients delayed diabetes induced by normal control and precluded diabetes induced by perforin-deficient spleen cells. In a CD8+ T cell-mediated model of diabetes, however, diabetes induced by adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus glycoprotein-specific CD8+ T cells was not delayed by the absence of TNFR1 in recipient mice. Together with the described expression patterns of perforin and TNF in the mononuclear islet infiltrates of NOD mice, these results indicate that two diabetogenic effector mechanisms are delivered by distinct cell populations: CD8+ T cells lyse β cells via perforin-dependent cytotoxicity, whereas CD4+ T cells, macrophages, and dendritic cells contribute to diabetes development via TNFR1-dependent β cell toxicity.

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

Reference59 articles.

1. Steinman, L.. 1995. Escape from “horror autotoxicus:” pathogenesis and treatment of autoimmune disease. Cell 80: 7

2. Tisch, R., H. McDevitt. 1996. Insulin-dependent diabetes mellitus. Cell 85: 291

3. Vyse, T. J., J. A. Todd. 1998. Genetic analysis of autoimmune diseases. Cell 85: 311

4. Makino, S., K. Kunimoto, Y. Muraoka, Y. Mizushima, K. Katagiri, Y. Tochino. 1980. Breeding of a non-obese diabetic strain of mice. Exp. Anim. 29: 1

5. Jarpe, A. J., M. R. Hickman, J. T. Anderson, W. E. Winter, A. B. Peck. 1991. Flow cytometric enumeration of mononuclear cell populations infiltrating the islets of Langerhans in prediabetic NOD mice: development of a model of autoimmune insulitits for type I diabetes. Regul. Immunol. 3: 305

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