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Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice¹

Wen Yang^2,*, Shabbir Hussain^*, Qing-Sheng Mi^3,*, Pere Santamaria and Terry L. Delovitch^4,*,

^* Autoimmunity/Diabetes Group, Robarts Research Institute, London, Ontario, Canada; Julia MacFarlane Diabetes Research Center, and Department of Microbiology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada

Activation-induced cell death (AICD) plays a key role in the homeostasis of the immune system. Autoreactive T cells are eliminated through AICD both from the thymus and periphery. In this study, we show that NOD peripheral T cells, especially CD8⁺ T cells, display a decreased susceptibility to anti-CD3-induced AICD in vivo compared with T cells from diabetes-resistant B6, nonobese diabetes-resistant, and NOD.B6Idd4 mice. The susceptibility of NOD CD8⁺ T cells to AICD varies in an age- and dose-dependent manner upon stimulation in vivo with either a mitogenic or nonmitogenic anti-CD3. NOD T cells preactivated by anti-CD3 in vivo are less susceptible than B6 T cells to TCR-induced AICD. Treatment of NOD mice with a mitogenic anti-CD3 depletes CD4⁺CD25^–CD62L⁺ but not CD4⁺CD25⁺CD62L⁺ T cells, thereby resulting in an increase of the latter subset in the spleen. Treatment with a nonmitogenic anti-CD3 mAb delays the onset of T1D in 8.3 TCR transgenic NOD mice. These results demonstrate that the capacity of anti-CD3 to protect NOD mice from T1D correlates with its ability to perturb T cell homeostasis by inducing CD8⁺ T cell AICD and increasing the number of CD4⁺CD25⁺CD62L⁺ T cells in the periphery.