TLR9 regulates tolerance of developing and mature anti-DNA B cells

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B601
Abstract ID: 5184

Presenting Author:
Kevin M Nickerson , Research Assistant Professor at Univ. of Pittsburgh Sch. of Med.

Abstract:

Autoreactive B cells can be tolerized by deletion, receptor editing, and anergy.  Nuclear antigen-specific B cells (such as anti-DNA) may be subject to unique regulation, as their autoantigens can also signal via Toll-like receptors 7 or 9. Indeed, we previously showed that anti-DNA B cells lacking TLR9 were not deleted, but instead became long-lived, yet anergic, follicular B cells. Here we report that the regulatory effect of TLR9 on anti-DNA development is not due to the Fas^lpr mutation. However, genetic background plays a role, as on the C57BL/6 background, TLR9 expression causes anti-DNA B cells to become developmentally arrested at the Fraction E to F transition in the spleen; whereas, in the autoimmune-prone MRL genetic background (regardless of Fas), such B cells progress to Fraction F. Further, we show via competitive mixed bone-marrow chimeras that TLR9 in the B cells themselves is necessary for these effects of TLR9, rather than indirectly by controlling anti-DNA Ab production, which can in turn affect self-DNA recognition. Mechanistically, RNAseq of B6 follicular anti-DNA B cells revealed that such B cells deficient in TLR9 are transcriptionally similar to edited—non-autoreactive—B cells and distinct from TLR9-intact anti-DNA cells. Hence, for anti-DNA B cells, TLR9 along with the BCR plays an important role in governing developmental progression, with TLR9 signals leading to a shorter half-life and developmental arrest.