T cell autoimmunity to histones and nucleosomes is a latent property of the normal immune system

Abstract

Objective. Investigators in this study undertook to determine whether in vitro antigen-responsive immune (polyomavirus T antigen [T-ag]-specific) and autoimmune (histone-specific) T cells from normal individuals share structural and genetic characteristics with those from patients with systemic lupus erythematosus (SLE).Methods. Histone-specific T cells were generated by stimulation of peripheral blood mononuclear cells (PBMCs) with nucleosome-T-ag complexes and were subsequently maintained by pure histones. T-agspecific T cell clones were initiated and maintained by T-ag. The frequencies of circulating histone-and T-agspecific T cells were determined in healthy individuals and in SLE patients by limiting dilution of PBMCs. T cell receptor (TCR) gene usage and variable-region structures were determined by complementary DNA sequencing. These sequences were compared between T-ag-and histone-specific T cells and between normal individuals and SLE patients for each specificity.Results. Individual in vitro-expanded histoneand T-ag-specific T cells from normal individuals displayed identical TCR V ␣ and/or V ␤ chain third complementarity-determining region (CDR3) sequences, indicating that they were clonally expanded in vivo. The frequencies of in vitro antigen-responsive T-ag-or histone-specific T cells from normal individuals were similar to those from SLE patients. Although heterogeneous for variable-region structure and gene usage, histone-specific T cells from healthy individuals and SLE patients selected aspartic and/or glutamic acids at positions 99 and/or 100 of the V ␤ CDR3 sequence. Conclusion. Autoimmune T cells from healthy individuals can be activated by nucleosome-T-ag complexes and maintained by histones in vitro. Such T cells possessed TCR structures similar to those from SLE patients, demonstrating that T cell autoimmunity to nucleosomes may be a latent property of the normal immune system.Experimental results consistently demonstrate that pathogenic autoimmune anti-DNA antibodies are secondary, antigen-driven, CD4ϩ T cell-dependent immune responses initiated by DNA itself (1-5). Since DNA most likely is not presented by antigen-presenting cells (APCs) in the context of HLA class II molecules, the contemporary paradigm favors DNA binding proteins as a sine qua non for generating T helper cell stimuli in the autoimmune anti-DNA antibody response (3,5,6). Such a hapten-carrier model, implying DNAspecific B cells and protein-specific T cells, enables the understanding of the molecular and the cellular basis for an immunoglobulin class switch and affinity maturation of anti-single-stranded DNA and anti-double-stranded DNA (anti-dsDNA) antibodies. Experimental and clinical results demonstrating that T cells specific for self or non-self DNA binding proteins may provide help for DNA-specific B cells support a model consistent with cognate B cell-T cell interaction (2,3,(6)(7)(8). So far, however, it is unclear how self-specific T cells may be initially activated. A priori, one would expect, for example, nuc...

Autoimmunity to DNA and Nucleosomes in Binary Tetracycline-Regulated Polyomavirus T-Ag Transgenic Mice

“…Provided T cells specific for T-Ag-derived peptides respond, these may indirectly activate autoimmune nucleosome-specific T cells by IL-2 released by such activated T cells. This scenario is consistent with previously published data (15,16,45). One observation obtained in tet-off group 4 mice may relate to presence of in vivo-activated autoimmune nucleosome-specific T cells.…”

“…Because productive infection depends on early expression of T-Ag (36, 37), a constitutive infection pattern reflects sustained T-Ag expression in vivo, and secondary to this also a constitutive binding of T-Ag to chromatin (14). If released from dying T-Agexpressing cells, such complexes have a demonstrable potential to induce anti-nucleosome and anti-DNA Abs (12) and to activate nucleosome-specific T cells (15,16). This indicates that productive polyomavirus infection-induced termination of tolerance to nucleosomal ligands may be biologically relevant as a model to investigate activation of B cell and T cell autoimmunity to dsDNA and nucleosomes.…”

“…The titers of the Abs determined in solid-phase (conventional anti-dsDNA ELISA) and in solution-phase anti-DNA ELISA (SPADE) using linear and circular dsDNA molecules, compared well with those currently determined in autoimmune (NZBϫW)F 1 mice (manuscript in preparation), and with those determined by the same solid-and solution-phase assays recently published for human SLE-derived anti-dsDNA Abs (27), which differ significantly from the much higher titers reported for Abs to nonself proteins or to Z DNA, as discussed by Stollar (43). The results of these experiments directly demonstrated that T-Ag expression initiated a process that resulted in continuous stimulation of autoimmune dsDNA-specific B cells, most probably due to release of heterologous nucleosome-T-Ag complexes able to initiate cognate interaction between DNA-specific B cells and T-Ag-specific T cells (13)(14)(15)(16)(17)44). The exact process involved in release of nucleosome-T-Ag complexes after expression of T-Ag is not fully determined, but may be caused by cytotoxic CD8 ϩ T cells activated in context of T-Ag expression.…”

“…45, and references therein), to terminate nucleosome-specific T cell anergy. The latter T cells progressed into functional, autoimmune T cells if nucleosome-derived, autologous peptides were properly presented by the same APC (a situation consistent with determinant spreading) (6,16). Both classes of T cells, either immune or autoimmune, may provide help for dsDNA-specific B cells to produce nephritogenic anti-dsDNA Abs (reviewed in Ref.…”

The Endoplasmic Reticulum Stress-Inducible Protein, Herp, Is a Potential Triggering Antigen for Anti-DNA Response

“…HMGB1-nucleosome complexes, but not HMGB1-free nucleosomes, induced antidsDNA and anti-histone IgG responses in BALB/c mice (38). Polyomavirus T Ag-nucleosome complex, but not nucleosomes, can elicit histone-specific T cells in healthy individuals in vitro (39). In this study, neither anti-oligonucleosome Abs nor antidsDNA Abs were elicited by immunization with oligonucleosomes.…”