The de novo revision of TCRα but not TCRβ is responsible for generating autoantibody-inducing CD4+ (aiCD4+) T cell that causes systemic autoimmunity, i.e., SLE (47.26)

Abstract

Abstract Objective: The induction of autoantibody-inducing CD4+ (aiCD4+) T cell after repeated immunization with antigen is the key for the induction of autoantibodies including anti-dsDNA antibody and immune tissue injury in SLE in our ‘self-organized criticality theory’. Here we investigated the mechanism for generating aiCD4+ T cell. Methods: BALB/c mice were immunized 8x with staphylococcul enterotoxin B (SEB). RAG1/2, TdT and pTα were detected using RT-PCR. Expression of GFP was studied in RAG-1/GFP knock-in mice. The rearranged intermediates of TCRα joining regions from 1 to 61 and all TCRβ variable and diversity regions were detected using LM-PCR. Histone modification of TCR loci was examined using ChIP assay. Results: RAG1/2, TdT pTα and were re-expressed in splenic T cell and expression of RAG1 gene was confirmed in vivo in RAG1/GFP knock-in mice after immunization 8x with SEB. The rearranged intermediates of TCRα joining region 12 were selectively induced in splenic Vβ8+CD4+ T cell after immunization 8x with SEB. Instead, rearranged intermediates of all TCRβ regions were never observed. The histone H3 of the TCR loci of splenic CD4+ T cell was heavily acetylated and trimethylated to the extent identical to thymocytes. Conclusion: As to the reason why TCRα gene was solely rearranged, since TCR gene loci were found to be always accessible and ready to TCR revision, we assume that TCR revision related to autoimmunity may be governed structurally by TCRβ molecule.