Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas
Moss, N.; Sakai, C.; Kaul, S. N.; Graybuck, L. T.; Rachid Zaim, S.; Angus-Hill, M. L.; He, Y. D.; Layton, E. D.; Bouvatte, P.; Wittig, P. J.; La France, C. M.; Peng, T.; Glass, M. C.; Krishnan, U.; Chander, A.; Kawelo, E. K.; Garber, J.; Reading, J.; Anover-Sombke, S. D.; Kwok, M.; Green, D. J.; Goldrath, A. W.; Sigvardsson, M.; Skene, P. J.; Li, X.-j.; Torgerson, T. R.; Kuan, E. L.
Show abstract
Interferons (IFNs) orchestrate diverse immune responses, but distinguishing individual IFN contributions in human transcriptomic data is challenging due to overlapping interferon-stimulated gene (ISG) signatures and limited cell-type-specific datasets. To address this, we generated a single-cell transcriptomic atlas of IFN responses by stimulating primary human T, B, NK, and CD14 monocytes with IFN-I, IFN-II, and IFN-III. This revealed core and cell-type-specific ISG programs across 13 subsets, highlighting distinct functions of IFNs. We developed an algorithm to separate IFN-I and IFN-II activity in transcriptomic data. Applied to multiple myeloma samples, it showed elevated IFN-I and IFN-II responses, with induction therapy reducing only IFN-I. Extending to multiple disease datasets provided a cross-disease overview of IFN-I and IFN-II activities and revealed increased IFN-II activities in T cells during lupus flares. This resource and the accompanying analytical framework enable dissection of IFN-driven transcriptional programs in a cell-type specific manner in human disease.
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