A Defect in Deletion of Nucleosome-Specific Autoimmune T Cells in Lupus-Prone Thymus: Role of Thymic Dendritic Cells

Abstract

To study central tolerance to the major product of ongoing apoptosis in the thymus, we made new lines of transgenic (Tg) mice expressing TCR of a pathogenic autoantibody-inducing Th cell that was specific for nucleosomes and its histone peptide H471–94. In the lupus-prone (SWR × NZB)F1 (SNF1) thymus, introduction of the lupus TCR transgene caused no deletion, but marked down-regulation of the Tg TCR and up-regulation of endogenous TCRs. Paradoxically, autoimmune disease was suppressed in the αβTCR Tg SNF1 mice with induction of highly potent regulatory T cells in the periphery. By contrast, in the MHC-matched, normal (SWR × B10. D2)F1 (SBF1), or in the normal SWR backgrounds, marked deletion of transgenic thymocytes occurred. Thymic lymphoid cells of the normal or lupus-prone mice were equally susceptible to deletion by anti-CD3 Ab or irradiation. However, in the steady state, spontaneous presentation of naturally processed peptides related to the nucleosomal autoepitope was markedly greater by thymic dendritic cells (DC) from normal mice than that from lupus mice. Unmanipulated thymic DC of SNF1 mice expressed lesser amounts of MHC class II and costimulatory molecules than their normal counterparts. These results indicate that apoptotic nucleosomal autoepitopes are naturally processed and presented to developing thymocytes, and a relative deficiency in the natural display of nucleosomal autoepitopes by thymic DC occurs in lupus-prone SNF1 mice.

Induced immune tolerance of autoantigen loaded immature dendritic cells in homogenic lupus mice

“…It was first confirmed that DCs induce immune tolerance in the central self-tolerance. Existing studies show that the injection of allogeneic DCs into the thymus of newborn mice induces immune tolerance (Michaels et al, 2005). Similar results were obtained in studies of bone marrow chimeras and transgenic mice.…”

Induction and maintenance of self tolerance: the role of CD4+CD25+ regulatory T cells

“…Self antigens (e.g. hemoglobin, C5 component of the complement pathway, lysozyme, and apoptotic nucleosomes) are constitutively processed and presented by antigen-presenting cells (APCs) [90,101,105,116,124,129,167,194,203]. Therefore, self determinants can also be categorized as dominant and non-dominant.…”

Animal Models of Molecular Pathology

“…301,308 This further suggested that a defect in Treg numbers or function may contribute to lupus pathogenesis. Moreover, it has been found that administration of tolerogenic peptides, such as pCons from anti-DNA IgG in NZB/W F1 mice 309 or histone peptide H471 in SNF1 mice, 310 ameliorated disease by expanding the Treg subset. Clearly, modulating Treg number and function might be a promising way to treat human SLE.…”