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.

doi:10.64898/2025.12.02.691676

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bioRxiv · 10.64898/2025.12.02.691676

Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas

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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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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.. 2025-12-05. Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas. https://doi.org/10.64898/2025.12.02.691676

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