Background/Purpose: In addition to TcR signaling and costimulation, CD8 T cells require a third signal to mature into effector cytotoxic T lymphocytes (CTL). In pathogen models, interferon alpha (IFN-a) and IL-12 can serve as signal 3. In the parent-into-F1 (P->F1) model, there are no exogenous pathogens yet B6->B6D2F1 mice exhibit robust donor anti-host CD8 CTL resulting in >90% elimination of host splenocytes i.e. acute graft-vs.-host disease (GVHD).  Transfer of the DBA parent (DBA->F1) results in DBA CD4-driven host B cell expansion and lupus (chronic GVHD) due to a failure of CD8 CTL supporting the idea that promoting CD8 CTL by enhancing signal 3 molecules may be beneficial in lupus.

Methods: Following donor cell transfer, host splenocytes were analyzed by real time PCR and flow cytometry. To promote signal 3 molecules, three TLR-9 simulating CpG ODNs (2006, 1826 or 2336) were administered to DBA->F1 mice (100 micrograms i.p.) during the first 5 days after transfer.

Results: For untreated DBA->F1 mice, there was no significant elevation of IL-12 gene expression and transient, low level (5-10 fold) elevations of IFN-a inducible (IFI) genes (MX-1, OAS-1) during the first two weeks after donor transfer. Long term, IFI gene expression in the setting of severe lupus renal disease was similarly low level for DBA->F1 mice. DBA->F1 mice receiving CpG ODN s exhibited a robust donor anti-host CD8 CTL response and profound host B cell elimination at two weeks for CpGs 2006 and 1826. CpG 2336 prevented chronic GVHD associated host B cell expansion but did not significantly reduce B cells below normal F1 values. Only CpGs 2006 and 1826 induced strong (30-60 fold) IL-12 and IFI-gene expression at 6 hours after administration to normal F1 mice supporting the idea that the ability of a TLR9 CpG ODN to induce CTL is related to its ability to induce signal 3 molecules IL-12 and/or IFN-a. Surprisingly, we found no evidence that either IL-12 or IFN-a are critical for the robust CD8 CTL response in B6->F1 mice. Acute GVHD phenotype was not significantly altered in BDF1 mice by transferring B6 donor T cells deficient in either IFN-a receptor or IL-12 receptor beta nor by treating with anti-IL-12 mAb however disease could be blocked by transferring B6 donor T cells deficient in TNF receptor 2 (TNFR2) but not TNFR1.

Conclusion: These results support the conclusion that in the absence of pathogens, failure of down regulatory CD8 CTL permits CD4 T cell driven lupus. Conversely, induction of IL-12 and/or IFN-a can rescue defective CD8 CTL in DBA->F1 mice and abort lupus raising the possibility that CTL promotion may be worthy of further study as a potential lupus treatment. Our results demonstrating a critical role for TNF in CD8 CTL responses in the absence of pathogens raise concerns that therapeutic TNF blockade in humans may impair CD8 CTL responses to non-pathogens (tumors, autoantigens) and raise the risk of certain tumors and humoral autoimmunity as described for some TNF-blocking agents.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-promotion-of-cd8-ctl-by-cpg-oligodeoxynucleotides-odn-in-an-induced-model-of-lupus/