Background/Purpose:  Previous studies strongly suggest that interferon α (IFNα) may be the principal driver of SLE, where increased IFNα and IFNα-regulated gene transcripts explain many of the immune alterations seen in SLE patients. However, the causal relationship between IFNα and SLE remains speculative and direct evidence for this causal link is required for more effective intervention of the disease. To directly prove the role of IFNα in inducing SLE, we generated transgenic (Tg) mice that express IFNα under the control of the inducible doxycycline (Dox) promoter.

Methods:  The mouse IFNα a1 (mIFNα) cDNA inserted downstream of the TetOp promoter of pTet Splice vector to generate TetOp-mIFNα. TetOp-mIFNα was microinjected into fertilized eggs of C57BL/6 mice to obtain TetOp-mIFNα Tg mice. The mice were mated with EμSR-tTA Tg mice (FVB/N background), expressing the Tet-transactivator (tTA) gene downstream of the Ig heavy chain enhancer and SRα promoter (Felsher and Bishop, Mol Cell 4:199, 1999), resulting in lymphoid cell-specific gene expression (EμSR-tTA) to produce double transgenic TetOp-mIFNα/EμSR-tTA mice of a C57BL6/FVBN background (IFNα Tg C57BL6/FVBN mice). These mice produced IFNα 4 weeks after cessation of 50 μg/mL of Dox. This IFNα Tg mice were also back-crossed to make IFNα Tg mice of C57BL/6 background to guarantee the universality of the result.

Results:  IFNα expression alone was sufficient to induce disease with characteristics identical to SLE, i.e., serum anti-double stranded DNA (dsDNA) antibody, immune complexes (IC) and tissue injury including glomerulonephritis accompanied by IC deposition, alopecia, epidermal liquefaction, positive lupus-band skin test and classical splenic onion-skin lesions. In these mice, activated CD3⁺CD4^–CD8^– double-negative T (DNT) cells, which were also TCRαβ⁺B220⁺CD1d-teteramer^–, expanded significantly. When transferred into naïve recipients, these DNT cells infiltrated to the glomeruli of transgenic mice and induced de novo glomerulonephritis and alopecia. These DNT cells had halted differentiation and massively accumulated at the DN1 stage in the thymus. The DNT cell was characterized by the over-expression of PD-1 and Helios, an indicator of autoreactive DNT cell of CD8 T cell origin as shown by Rodriguez-Rodriguez N et al (J Immunol 194:4207, 2015).

Conclusion:  The results show that increased expression of IFNα is sufficient to induce SLE, and that DNT cell expressing PD-1 and Helios may play important roles in lupus tissue injury. The study is in collaboration with Dr. Dean W Felsher (Stanford University, Division of Oncology, Department of Medicine and Pathology).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/double-negative-t-dnt-cell-over-expressing-pd-1-and-helios-is-responsible-for-lupus-tissue-injury-in-systemic-lupus-erythematosus-sle-direct-proof-that-increased-interferon-alpha-ifn%ce%b1-expr/