Myeloid-Derived Suppressor Cell-Derived Interferon-β Promotes T Follicular Helper Cell Response and Exacerbates Lupus Development.

OBJECTIVE

Increasing evidence highlights a critical role of T follicular helper (Tfh) cells in autoimmune pathogenesis. This study aimed to identify inflammatory cytokines involved in driving Tfh cell responses in systemic lupus erythematosus (SLE).

METHODS

The circulating Tfh frequencies and interferon (IFN)-β levels were analyzed for correlations with disease activities in patients with SLE. Both lupus mice with IFN-β treatment and Ifnar1-/- mice with lupus induction were assessed for Tfh cell responses and disease progression. Sorting-purified naive CD4+T cells from Ifnar1-/- mice were adoptively transferred to lupus mice for monitoring Tfh cell differentiation in vivo. In culture, mouse CD4+T cells treated with IFN-β were examined for Tfh cell differentiation and intracellular signaling pathway. The underlying mechanism for IFN-β secretion by myeloid-derived suppressor cells (MDSCs) was investigated by co-immunoprecipitation and Western blotting.

RESULTS

We found that increased Tfh cells with IFN-I-inducible gene signatures correlated with disease activities in patients with SLE. Consistently, IFN-β treatment markedly enhanced Tfh cell response and exacerbated disease progression in lupus mice. Moreover, mice with IFNAR1 deficiency exhibited attenuated lupus progression with significantly decreased Tfh response. Mechanistically, IFN-β activated the indoleamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor (IDO/Kyn/AhR) axis to promote Tfh cell differentiation. Notably, expanded MDSCs in lupus were found to produce high levels of IFN-β. Further studies showed that the autoantigen activated lymphocyte-derived DNA stimulated IFN-β production by MDSCs via the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING)-dependent pathway.

CONCLUSION

These results have demonstrated a novel function of IFN-β in promoting Tfh cell response during lupus progression, which may facilitate the identification of new therapeutic targets for the treatment of SLE.