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Divergent transcriptional programming of class-specific B cell memory by T-bet and RORα

Abstract

Antibody class defines function in B cell immunity, but how class is propagated into B cell memory remains poorly understood. Here we demonstrate that memory B cell subsets unexpectedly diverged across antibody class through differences in the effects of major transcriptional regulators. Conditional genetic deletion of the gene encoding the transcription factor T-bet selectively blocked the formation and antigen-specific response of memory B cells expressing immunoglobulin G2a (IgG2a) in vivo. Cell-intrinsic expression of T-bet regulated expression of the transcription factor STAT1, steady-state cell survival and transcription of IgG2a-containing B cell antigen receptors (BCRs). In contrast, the transcription factor RORα and not T-bet was expressed in IgA+ memory B cells, with evidence that knockdown of RORα mRNA expression and chemical inhibition of transcriptional activity also resulted in lower survival and BCR expression of IgA+ memory B cells. Thus, divergent transcriptional regulators dynamically maintain subset integrity to promote specialized immune function in class-specific memory B cells.

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Figure 1: B cell–intrinsic T-bet is required for IgG2a formation.
Figure 2: T-bet is required for the survival and function of memory B cells in vivo.
Figure 3: T-bet expression during antigen-specific IgG2a memory development.
Figure 4: Evidence for T-bet activity in IgG2a+ memory B cells.
Figure 5: B cell–intrinsic T-bet is required for survival, expression of an IgG2a-containing BCR and function.
Figure 6: Separable programs for IgG2a+ and IgA+ memory B cells.
Figure 7: RORα regulates survival and BCR expression in IgA+ memory B cells.

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Acknowledgements

We thank B. Beutler (The Scripps Research Institute) for mice with the Domino mutation of Stat1; and N. Cereb, S.Y. Yang and L. Boring for assistance with construction of the loxP-flanked Tbx21 allele. Supported by the US National Institutes of Health (TL1 RR025772-03 to N.S.W.; AI042370 and AI076458 to S.L.R; DK080201 and MH092769 to T.P.B.; and AI047231, AI040215 and AI071182 to M.G.M.-W.), the Swiss National Science Foundation (S.L.O.), Novartis Jubliaeumsstiftung (S.L.O.) and the Roche Research Foundation (S.L.O.). This is manuscript 21154 from The Scripps Research Institute.

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N.S.W., L.J.M.-W. and M.G.M.-W. conceived of and designed the project; N.S.W. did all experiments and analyzed the data for all experiments; L.J.M.-W. identified T-bet in memory B cells and contributed to the preparation of the manuscript; S.L.O. contributed to experimental design; S.L.R. provided Tbx21F/F mice; T.P.B. provided SR1001; and N.S.W. and M.G.M.-W. wrote the manuscript.

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Correspondence to Michael G McHeyzer-Williams.

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Wang, N., McHeyzer-Williams, L., Okitsu, S. et al. Divergent transcriptional programming of class-specific B cell memory by T-bet and RORα. Nat Immunol 13, 604–611 (2012). https://doi.org/10.1038/ni.2294

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