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Peripheral Tolerance to a Nuclear Autoantigen: Dendritic Cells Expressing a Nuclear Autoantigen Lead to Persistent Anergic State of CD4⁺ Autoreactive T Cells After Proliferation¹

Kimito Kawahata^*, Yoshikata Misaki^2,*, Michiko Yamauchi^*, Shinji Tsunekawa, Keigo Setoguchi^*, Jun-ichi Miyazaki and Kazuhiko Yamamoto^*

^* Department of Allergy and Rheumatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan; Medical and Biological Laboratories, Ina, Japan; and Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Suita, Japan

It remains unknown why the T cell tolerance to nuclear autoantigens is impaired in systemic autoimmune diseases. To clarify this, we generated transgenic mice expressing OVA mainly in the nuclei (Ld-nOVA mice). When CD4⁺ T cells from DO11.10 mice expressing a TCR specific for OVA_323–339 were transferred into Ld-nOVA mice, they were rendered anergic, but persisted in vivo for at least 3 mo. These cells expressed CD44^high, CD45RB^low, and were generated after multiple cell divisions, suggesting that anergy is not the result of insufficient proliferative stimuli. Whereas dendritic cells (DCs) from Ld-nOVA (DCs derived from transgenic mice (TgDCs)), which present rather low amount of the self-peptide, efficiently induced proliferation of DO11.10 T cells, divided T cells stimulated in vivo by TgDCs exhibited a lower memory response than T cells stimulated in vitro by peptide-pulsed DCs. Furthermore, we found that repeated transfer of either TgDCs or DCs derived from wild-type mice pulsed with a lower concentration of OVA_323–339 induced a lower response of DO11.10 T cells in Ag-free wild-type recipients than DCs derived from wild-type mice. These results suggest that peripheral tolerance to a nuclear autoantigen is achieved by continuous presentation of the self-peptide by DCs, and that the low expression level of the peptide might also be involved in the induction of hyporesponsiveness.

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