Weak TCR signaling due to repeated immunization with antigen is the key for peripheral TCR revision generating aiCD4 T cell: a novel self-organized criticality theory (P4537)

Abstract

The autoimmune disease theory explains that autoreactive clones derive from restricted clones either slipped from thymic selection or reactivated from tolerance, which cannot explain varieties of autoantibody exceeding 140 specificities seen in SLE. We instead show that autoreactive clones newly emerge via de novo TCRalpha but not beta revision at periphery from thymus-passed non-autoreactive clones (PLoS ONE 4(12):e8382,2009). This autoreactive autoantibody-inducing CD4 (aiCD4) T cell stimulates B cells to generate autoantibodies and helps to generate CD8 CTL via antigen cross-presentation and cause SLE. We studied how aiCD4 T cell is produced. Methods: Balb/c mice were immunization 8x with staphylococcus enterotoxin B (SEB), signaling molecules and their phosphorylation were assayed using western blot and antibodies. Results: The chromatin of CD4 T cell V,J region was not acetylated/ H3K4me3-lated and open, thereby facilitating the access of RAG1/2. Upon repeated immunization 8x with SBE, RAG1/2 was up-regulated but CD3zeta, ZAP70, LAT, SLP-76, PLCgamma1 and NFAT1/2 were down-regulated in splenic Vbeta8+CD4 T cell. Instead, re-activation of RAG1/2 was inhibited when TCR signal was augmented vice versa by adding PMA+ionomycin, indicating that loss of TCR signal reactivates RAG1/2 at peripheral lymphoid organ in spleen. Conclusion: Weak TCR signaling due to repeated immunization with antigen re-expresses RAG1/2 at periphery to induce aiCD4 T cell and cause SLE.