ZBTB32 restrains antibody responses to murine cytomegalovirus infections, but not other repetitive challenges

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.

Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure

“…For example, the transcription factor ZBTB32 specifically limits the magnitude and duration of memory B cell responses, perhaps to keep chronic infections from overwhelming the system (Jash et al, 2016(Jash et al, , 2019. It remains to be established whether such mechanisms may be .…”

“…Memory responses, especially by isotype-switched B cells, are directed by fundamentally distinct transcriptional programs than those of naïve cells ( Bhattacharya et al, 2007 ; Jash et al, 2016 ; Wang et al, 2012 ; Zuccarino-Catania et al, 2014 ). For example, the transcription factor ZBTB32 specifically limits the magnitude and duration of memory B cell responses, perhaps to keep chronic infections from overwhelming the system ( Jash et al, 2016 , 2019 ). It remains to be established whether such mechanisms may be selectively operating on SARS-CoV-2 and other coronavirus N antibody responses due to their antigenic similarity between strains.…”

Antibody Responses to SARS-CoV-2: Let’s Stick to Known Knowns

“…Importantly, similar to responses seen during a primary infection, these memory B cells generate the transiently induced extrafollicular "emergency" Ab responses, likely driven by the same inflammatory signals that initiated these responses during a primary infection, but now derived from a previously selected and clonally expanded population of B cells. Recall responses may also be driven in part by transcriptional programs that bias toward transience more so than primary responses (61)(62)(63). The distinction between primary and memory B cell responses becomes particularly important in the context of prior coronavirus studies.…”

ZBTB38 is dispensable for hematopoiesis and antibody responses

“…Deficiencies in two other BTB-ZF factors, ZBTB20 and ZBTB32, cause profound effects on plasma cell lifespan despite modest changes in gene expression [10-13]. Therefore, to determine if ZBTB38 has a functional role in primary B cell responses, we first examined GC reactions.…”