Type I interferon dynamics determines memory B cell epigenetic identity in chronic viral infection

Cooper, L.; Xu, H.; Polmear, J.; Szeto, C.; Pang, E. S.; Gupta, M.; Taylor, J. J.; Jackson, K. J. L.; Nguyen, A.; La Gruta, N.; Martelotto, L. G.; Parish, I. A.; O'Keeffe, M.; Scharer, C. D.; Gras, S.; Good-Jacobson, K. L.

doi:10.1101/2023.03.02.530850

bioRxiv · 10.1101/2023.03.02.530850

Type I interferon dynamics determines memory B cell epigenetic identity in chronic viral infection

Cooper, L.·Xu, H.·Polmear, J.·Szeto, C.·Pang, E. S.·Gupta, M.·Taylor, J. J.·Jackson, K. J. L.·Nguyen, A.·La Gruta, N.·Martelotto, L. G.·Parish, I. A.·O'Keeffe, M.·Scharer, C. D.·Gras, S.·Good-Jacobson, K. L.

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Abstract

Memory B cells are key providers of long-lived immunity against infectious disease, yet in chronic viral infection they do not produce effective protection. How chronic viral infection disrupts memory B cell development, and whether such changes are reversible, remains unknown. Here, we uncover type-I interferon (IFN-I) dynamics as a key determinant in shaping chronic memory B cell development. Through single-cell (sc)ATAC-sequencing and scRNA-sequencing, we identified a unique memory subset enriched for IFN-stimulated genes (ISGs) during chronic lymphocytic choriomeningitis virus infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic memory B cells, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing a phenotypic change in the dominating memory B cell subset. However, timing was critical, with memory B cells resistant to intervention after 4 weeks post-infection. Together, our research identifies a key mechanism to instruct memory B cell identity during viral infection. One Sentence Summary: IFN dynamics in chronic versus acute viral infection determines memory B cell development.

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Cooper, L., Xu, H., Polmear, J., Szeto, C., Pang, E. S., Gupta, M., Taylor, J. J., Jackson, K. J. L., Nguyen, A., La Gruta, N., Martelotto, L. G., Parish, I. A., O'Keeffe, M., Scharer, C. D., Gras, S., Good-Jacobson, K. L.. 2023-03-02. Type I interferon dynamics determines memory B cell epigenetic identity in chronic viral infection. https://doi.org/10.1101/2023.03.02.530850

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