Biology subjects

Peyton, L.

Publications and source records attributed to Peyton, L..

5 recordsLinked to original sources

bioRxiv2026

Maternal vaccination timing shapes the composition and maturation of antibody clonotypes transferred to the newborn

Newborns rely on maternally transferred antibodies for immune protection, acquired across the placenta and through breast milk. Despite this importance, how closely the inherited antibody repertoire resembles the mothers has not been examined at the clonotypic level. We combined BCR-Seq with proteomic Ig-Seq to track SARS-CoV-2-specific antibody clonotypes across maternal blood, cord blood, and breast milk from six mRNA-immunized pregnant individuals. Vaccination earlier in gestation generated more diverse peak IgG repertoires but greater contraction before delivery, yielding fewer transferred clonotypes. Vaccination later in gestation produced more restricted peak repertoires, but more clonotypes persisted to delivery and transferred to cord. Infant cord was enriched for persistent, highly somatically mutated, and intraclonally diverse IgG clonotypes, consistent with preferential transfer of affinity-matured antibodies. In contrast, breast milk IgA repertoires were largely distinct from systemic repertoires and underwent substantial remodeling despite stable antigen titers. These findings define molecular determinants of passive immunity shaped by vaccination timing relevant to optimizing maternal immunization.

immunology↗

bioRxiv2026

Female iPSC X-chromosome inactivation (XCI) erosion and its transcriptomic effects during CRISPR gene editing and neural differentiation

Human induced pluripotent stem cells (hiPSC) and iPSC-differentiated neural cells, in combination with CRISPR editing, are commonly used for studying neurodevelopmental and other brain disorders. Female iPSCs undergo random X-chromosome inactivation (XCI) via epigenetic silencing by noncoding X inactive specific transcript (XIST). It is known that female iPSCs may lose XIST expression, leading to XCI erosion that affects both X-linked and autosomal gene expression. However, the effects of CRSIPR editing and neural differentiation on XCI erosion in iPSC-derived neurons and how this may confound a real-world transcriptomic analysis of differentially expressed genes (DEGs) are poorly understood. Here, leveraging bulk RNA-seq of hundreds of CRISPR-edited female iPSC lines from four donor lines for 66 genes and single-cell RNA-seq of iPSC-derived neurons of a subset of 42 edited genes, we investigated the effects of XCI erosion during CRISPR editing and in iPSC-derived neurons. We found that XCI erosion was variable in CRISPR-edited female iPSCs and largely preserved in iPSC-derived neurons. Like in iPSCs, XIST in neurons predominately influenced the expression of X-linked genes; however, its effect on autosomal genes was more pronounced in single neurons. Mechanistically, XIST epigenetically causes allelic imbalance of both X-linked and autosomal genes, with the former showing stronger allele-specific expression (ASE) bias. Notably, XIST-induced ASE bias exhibited a conserved positional pattern at loci affecting neurodevelopmental genes across different female lines and cell types. Finally, we demonstrated a confounding effect of XCI erosion on DEG analyses in iPSC-derived neurons. These results have significant implications in hiPSC modeling of neurodevelopmental and other brain disorders.

genomics↗

bioRxiv2024

Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryo-EM structure of RHA10 with HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting glycan deletions in infecting SHIVs could consistently induce CD4bs bNAbs. To test this, we constructed SHIV.CH505.D3 with CD4bs-proximal glycan deletions. Infection of 10 macaques resulted in accelerated CD4bs bNAb responses in 8, compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and thus serve as a model for HIV vaccine design. HighlightsO_LIOut of 115 wildtype HIV-1 Env bearing SHIV infected macaques, only one macaque (T681) developed CD4bs bNAbs C_LIO_LICD4bs bNAbs in macaque T681 recognized Env similarly to previously described CDR-H3 dominated human CD4bs bNAbs and exhibited comparable breadth and potency C_LIO_LITransient CD4bs-proximal glycan deletions in macaque T681 preceded bNAb induction C_LIO_LIA novel SHIV with CD4bs-proximal glycan holes and enhanced CD4bs antigenicity immunofocused B cell responses to the CD4bs and elicited cross-clade neutralizing responses in 80% of macaques C_LI

microbiology↗

bioRxiv2024

mRNA-based influenza vaccine expands breadth of B cell response in humans

Summary paragraphEliciting broad and durable antibody responses against rapidly evolving pathogens like influenza viruses remains a formidable challenge1,2. The germinal center (GC) reaction enables the immune system to generate broad, high-affinity, and durable antibody responses to vaccination3-5. mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines induce persistent GC B cell responses in humans6-9. Whether an mRNA-based influenza vaccine could induce a superior GC response in humans compared to the conventional inactivated influenza virus vaccine remains unclear. We assessed B cell responses in peripheral blood and draining lymph nodes in cohorts receiving the inactivated or mRNA-based quadrivalent seasonal influenza vaccine. Participants receiving the mRNA-based vaccine produced more robust plasmablast responses and higher antibody titers to H1N1 and H3N2 influenza A viruses and comparable antibody titers against influenza B virus strains. Importantly, mRNA-based vaccination stimulated robust recall B cell responses characterized by sustained GC reactions that lasted at least 26 weeks post-vaccination in three of six participants analyzed. In addition to promoting the maturation of responding B cell clones, these sustained GC reactions resulted in enhanced engagement of low-frequency pre-existing memory B cells, expanding the landscape of vaccine-elicited B cell clones. This translated to expansion of the serological repertoire and increased breadth of serum antibody responses. These findings reveal an important role for the induction of persistent GC responses to influenza vaccination in humans to broaden the repertoire of vaccine-induced antibodies.

immunology↗

bioRxiv2022

Convergent epitope specificities, V gene usage and public clones elicited by primary exposure to SARS-CoV-2 variants

An important consequence of infection with a SARS-CoV-2 variant is protective humoral immunity against other variants. The basis for such cross-protection at the molecular level is incompletely understood. Here we characterized the repertoire and epitope specificity of antibodies elicited by Beta, Gamma and ancestral variant infection and assessed their cross-reactivity to these and the more recent Delta and Omicron variants. We developed a high-throughput approach to obtain immunoglobulin sequences and produce monoclonal antibodies for functional assessment from single B cells. Infection with any variant elicited similar cross-binding antibody responses exhibiting a remarkably conserved hierarchy of epitope immunodominance. Furthermore, convergent V gene usage and similar public B cell clones were elicited regardless of infecting variant. These convergent responses despite antigenic variation may represent a general immunological principle that accounts for the continued efficacy of vaccines based on a single ancestral variant.

immunology↗