Analysis of Immunological Tolerance to a nuclear autoantigen using transgenic mcie.

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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 three months. 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 (TgDCs) efficiently induced proliferation of DO11.10 T cells, divided T cells stimulated by TgDCs in vivo exhibited a lower memory response than T cells stimulated by peptide-pulsed DCs. Furthermore, repeated transfer of TgDCs induced hyporesponsiveness of DO11.10 T cells in antigen-free wild-type recipients, suggesting that the repeated encounters with TgDCs rendered DO11.10 T cells persistent anergy. Since the state of TgDCs and peptide-pulsed DCs was almost the same except for the expression level of the agonistic ligand, the property of nuclear autoantigens which controls the tolerance of CD4^+ T cells might be the low and continuous expression of a self-peptide on DCs.