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bioRxiv · 10.1101/2021.06.10.447979

PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

Dufaud, C. R.·Shuparski, A. G.·Higgins, B. W.·McHeyzer-Williams, L. J.·McHeyzer-Williams, M. G.
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Abstract

Adaptive B cell immunity to environmental antigens must be regulated by multiple CD4 T cell dependent tolerance mechanisms. Using integrated single cell strategies, we demonstrate that acute PD-1 blockade induces extensive and selective local anti-inflammatory IgG1 plasma cell (PC) differentiation. Expansion of pre-existing IgG1 germinal center (GC) B cell and enhanced GC programming without memory B cell involvement reveals an isotype-specific GC checkpoint that blocks steady-state IgG1 antibody maturation. While there was no adjuvant impact on immunization, acute PD-1 checkpoint blockade exaggerates anti-commensal IgG1 antibody production, alters microbiome composition and exerts its action in a CD4 T cell dependent manner. These findings reveal a PD-1 controlled adaptive B cell tolerance checkpoint that selectively constrains maturation of pre-existing anti-inflammatory antibodies to prevent over-reaction to steady-state foreign antigens. In BriefPD-1 controls an adaptive B cell tolerance checkpoint in steady-state germinal centers to inhibit the maturation and production of IgG1 antibody with pre-existing foreign specificities. Highlights- Acute PD-1 blockade induces extensive IgG1 PC differentiation at homeostasis - PD-1 blockade releases an IgG1 GC B cell checkpoint that drives expansion and PC formation - No adjuvant effect on foreign antigen but expansion of pre-existing IgG1 specificities to non-self - PD-1 exerts CD4 T cell dependent tolerance in the GC to restrict IgG1 maturation to non-self Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/447979v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@488f86org.highwire.dtl.DTLVardef@1c6b0d1org.highwire.dtl.DTLVardef@1827dbdorg.highwire.dtl.DTLVardef@d375b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Dufaud, C. R., Shuparski, A. G., Higgins, B. W., McHeyzer-Williams, L. J., McHeyzer-Williams, M. G.. 2021-06-10. PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens. https://doi.org/10.1101/2021.06.10.447979

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