Background/Purpose:

We found in reproducible experiments in which the mice not prone to autoimmune disease were immunized repeatedly with antigen that overstimulation of CD4 T cells led to the development of aiCD4 T cell which had undergone TCR revision capable of inducing varieties of autoantibody and antigen-specific CTL via antigen cross-presentation, after which they caused SLE (Tsumiyama K et al., 2009). Here we identify aiCD4 T cell as DOCK8+CD4 T cell.

Methods:

aiCD4 T cell was searched by transferring different fractions of CD4 T cells of x12 OVA-immunized BALB/c female mice into naïve mice and tested if autoantibodies were raised, mass spectrometry, and FACS.

Results:

We focused CD45RB^lo CD122^lo PD-1+CD4 T cell as aiCD4 T candidate, and its membrane uniquely expressed DOCK8. DOCK8+CD4 T cell was a large lymphocyte with abundant ER and mitochondria, ICOS+ CXCR5- PD1+ Ly6C+ LFA1+, produced increased IFNg, IL-4, IL-6, IL-17 and IL-21, and its TCR repertoire was deviated. Upon transfer to naïve mice or to the x8 OVA-pre-immunized and CD4 T-depleted mice in which CTL was yet immature, DOCK8+CD4 T cells induced SLE, where anti-dsDNA/ Sm Ab, glomerulonephritis of WHO IV/V types (Table, upper), skin liquefaction degeneration, splenic periarteriolar fibrosis with amyloid-like deposits classical of Onion-skin lesion, pericholangitis, pneumonitis, thyroiditis, perineuritis and panniculitis developed. Manifestations including kidney disease (Table, lower) were cured by anti-DOCK8 Ab treatment.

Conclusion:

We prove the self-organized criticality theory explaining that autoimmunity arises as a natural consequence of routine but exaggerated immune response against antigen when stimulated maximally beyond immune systemfs self-organized criticality and show that DOCK8+CD4 T cell causes SLE.