T cell lines specific for polyomavirus T‐antigen recognize T‐antigen complexed with nucleosomes: a molecular basis for anti‐DNA antibody production

Abstract

We have previously demonstrated that in vivo expression of the polyomavirus DNA‐binding T‐antigen initiated production of IgG antibodies to T‐antigen and to DNA, but not to a panel of autoantigens not related to nucleosomes, indicating an antigen‐selective T cell‐dependent B cell response. In this study, we demonstrate that CD4‐positive T cells from both normal and systemic lupus erythematosus (SLE) patients readily proliferate in response to pure T‐antigen, and also to T‐antigen in complex with nucleosomes. T‐antigen‐specific T cell lines from both normal individuals and SLE patients proliferate in response to nucleosome‐T‐antigen complexes, but not to nucleosomes or histones. B cells co‐cultured with T‐antigen‐specific T cells and stimulated with nucleosome‐T‐antigen complexes produce anti‐T‐antigen and anti‐DNA antibodies, indicating that such CD4‐positive T cells have the potential to interact with B cells specific for individual components of nucleosome‐T‐antigen complexes. Thus, a non‐self DNA‐binding protein like polyomavirus T‐antigen may initiate and maintain an antibody response to DNA when T‐antigen is actively expressed.

B cell epitope of human cytomegalovirus phosphoprotein 65 (HCMV pp65) induced anti-dsDNA antibody in BALB/c mice

“…The binding of pp65 to metaphase-arrested chromosomes in pp65-expressing fibroblasts during virus infection implies that pp65 may not bind to host proteins, but also forms immune-complex to genetic materials and nuclear components [42]. The SV40 large T-antigen of human polyomaviruses has been demonstrated to form a T-antigen/nucleosome complex, subsequently targeted by host immune responses and accelerates the generation of cross-reactive antibodies against both virus and host during viral replication [43]. Therefore, full-length or fragmented pp65 binding to immune-complexes formed from nuclear binding proteins may not only be targeted by antiviral antibodies but also increase the opportunity for B cell epitope spreading and lead to autoimmunity in genetically susceptible individuals.…”

Fragment of tegument protein pp65 of human cytomegalovirus induces autoantibodies in BALB/c mice

“…The T-antigen of human polyomaviruses has been shown to complex with nucleosomes of infected cells during viral replication. These nucleosomes/T-antigen complexes are subsequently targeted by immune responses and become a catalyst for cross-reactive antibodies against both virus and host [35]. At HCMV infection, pp65 is imported to the nucleus immediately via two nuclear localization sequences: pp65 418-438 and pp65 537-561 [36].…”

Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis

“…For these analyses, we used nucleosomes stripped for non-histone proteins, and nucleosomes generated by micrococcal nuclease digestion of chromatin,22 with structures and a size distribution similar to apoptotic nucleosomes as they appear in the context of apoptosis.…”

“…Nucleosomes were prepared from a murine fibroblast cell line and characterised as described previously 21 22. SN was shown to contain the core histones H2A, H2B, H3 and H4, while Nuc contained all histone classes and several non-histone proteins.…”