Abstract
ZBTB32 is a transcription factor that is highly expressed by a subset of memory B cells and restrains the magnitude and duration of recall responses against hapten-protein conjugates. To define physiological contexts in which ZBTB32 acts, we assessed responses by Zbtb32−/− mice or bone marrow chimeras against a panel of chronic and acute challenges. Mixed bone marrow chimeras were established in which all B cells were derived from either Zbtb32−/− mice or control littermates. Chronic infection of Zbtb32−/− chimeras with murine cytomegalovirus led to nearly 20-fold higher antigen-specific IgG2b levels relative to controls by week 9 post-infection, despite similar viral loads. In contrast, IgA responses and specificities in the intestine, where memory B cells are repeatedly stimulated by commensal bacteria, were similar between Zbtb32−/− mice and control littermates. Finally, an infection and heterologous booster vaccination model revealed no role for ZBTB32 in restraining primary or recall antibody responses against influenza viruses. Thus, ZBTB32 does not limit recall responses to a number of physiological acute challenges, but does restrict antibody levels during chronic viral infections that periodically engage memory B cells. This restriction might selectively prevent recall responses against chronic infections from progressively overwhelming other antibody specificities.
Highlights
ZBTB32 is a transcription factor that is highly expressed by a subset of memory B cells and restrains the magnitude and duration of recall responses against hapten-protein conjugates
We recently demonstrated that in the absence of ZBTB32, recall responses to T cell-dependent model antigens were much more rapid and durable than those mounted by control memory B cells[8]
ZBTB32 is highly expressed by isotype-switched memory B cells, both in mice and humans[6,8,9,11]
Summary
ZBTB32 is a transcription factor that is highly expressed by a subset of memory B cells and restrains the magnitude and duration of recall responses against hapten-protein conjugates. ZBTB32 does not limit recall responses to a number of physiological acute challenges, but does restrict antibody levels during chronic viral infections that periodically engage memory B cells. Upon clearance of infections or vaccines, a pool of antigen-specific lymphocytes remains, poised to rapidly respond to immunogen re-exposure When these memory lymphocytes are subsequently engaged by their cognate immunogens, the resulting recall responses are typically of greater magnitude and rapidity than the antecedent primary reaction. We reasoned that chronic infections would be most likely to reveal such effects of ZBTB32 deficiency on memory B cell activation and plasma cell survival
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