PAX5 is the master transcription factor controlling B cell identity. In humans, mutations in PAX5 account for 30% of B cell acute lymphoblastic leukemia (B-ALL) cases. Investigating the causal effects of PAX5 mutations has however been difficult due to the premature lethality of Pax5−/− mice. Here we describe a novel mouse strain with a premature STOP mutation in Pax5 (Y351*) that produces a truncated protein and reduction in protein function, yet still allows for some B cell development to occur. A population of uncommitted and multipotent CD19+B220− B cells develops in the bone marrow of homozygous mice leading to the development of B-ALL. We show that the tumors frequently acquire secondary mutations in Jak3, and Ptpn11 highlighting key pathways interacting with PAX5 during malignant transformation. Analysis of the PAX5Y351* mice provide insight not only into the functional consequence of reduced PAX5 activity on B cell development and identity, but also provides an avenue in which to study PAX5-driven B-ALL in mice.One Sentence SummaryReduction in PAX5 function in mice induces the development of uncommitted B cells that have multipotent and malignant potential.
23Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. 24Here we show that antibody titres to a key target, the repeat region of the Plasmodium 25 falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical 26 trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting 27 vaccine responsiveness, we developed Ig-knockin mice with elevated numbers of PfCSP-binding 28 B cells. We determined that recall responses were inhibited by antibody feedback via epitope 29 masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that 30 prevents boosting is below the amount of antibody required for protection. Finally, while 31 antibody feedback limited responses to the PfCSP-repeat region in vaccinated volunteers, 32 potentially protective subdominant responses to C-terminal regions did expand with subsequent 33 boosts. These data suggest that antibody feedback drives the diversification of immune responses 34 and that vaccination for malaria will require the targeting of multiple antigens. 35 36 6 . Anti-(NANP)n repeat responses saturate after 2 immunizations and a booster at 18 months 55 provides only a modest increase in antibody and protection 4, 5, 6, 7 . 56 57 An alternative vaccine approach has been to develop an attenuated whole parasite vaccine using 58 radiation attenuated P. falciparum sporozoites (PfSPZ) 8 . This vaccine confers sterile protection 59 in malaria-naïve individuals for ~1 year which is thought to be mediated largely by T cells in the 60 liver 8, 9, 10, 11 . However, there is also evidence that PfSPZ Vaccine-induced antibodies may have 61 some short-term protective role and utility as a correlate of protection 8, 10 . 62 63 Given the limited capacity of these current malaria vaccine approaches to induce sustained 64 antibody mediated protection, it is critical to determine the mechanisms underlying B cell 65 responses to Plasmodium sporozoites and PfCSP in particular 12, 13, 14, 15 . Analysis of antibody 66 titer, breadth and single cell antigen specific B cell responses to RTS,S and PfSPZ vaccines in 67 humans provides critical hypothesis generating data for developing mouse models to establish 68 mechanisms 8, 10, 16, 17, 18 . Here we show that following immunization with PfSPZ Vaccine in 69 humans, B cells lose responsiveness after 2 vaccinations. To dissect the mechanism of this non-70 responsiveness in vivo, we developed Ig-knockin mice specific for PfCSP that facilitate tracking 71 of the B cell responses to PfCSP. The data reported herein show that the lack of B cell boosting 72 was mediated by antibody feedback by repeat-specific antibodies. However, boosting led to the 73 emergence of subdominant epitopes and increased the diversity of the antibody response over 74 time. This suggests that effective vaccination may depend on inducing responses to a diverse 75 range of protective epitopes. 76Analysis of the antibody sequences revealed that the level ...
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