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

Abstract

SUMMARYMemory 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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“…The Decoy tetramer was prepared as previously described 42 . The COVID‐19‐specific B cell tetramer was prepared as previously described, 42 by conjugating the biotinylated HexaPro spike protein to SAV‐PE (Cat: PJRS25, Agilent [formerly ProZyme], CA, USA) at a concentration ratio of 4:1 respectively.…”

“…The Decoy tetramer was prepared as previously described. 42 The COVID‐19‐specific B cell tetramer was prepared as previously described, 42 by conjugating the biotinylated HexaPro spike protein to SAV‐PE (Cat: PJRS25, Agilent [formerly ProZyme], CA, USA) at a concentration ratio of 4:1 respectively. During flow cytometric analysis, cells that bind to the HexaPro spike protein tetramer as well as the Decoy SAV‐PE*DL650 tetramer were considered Decoy‐specific and excluded from further analysis.…”