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A novel humanized mouse model with significant improvement of class- switched, antigen-specific antibody production

Hua Yu, Chiara Borsotti, Jean-Nicolas Schickel, Shu Zhu, Till Strowig, Elizabeth E. Eynon, Davor Frleta, Cagan Gurer, Andrew J. Murphy, George D. Yancopoulos, Eric Meffre, Markus G. Manz and Richard A. Flavell

Key points

  • Human IL6 improves T cell engraftment and serum IgG production in humanized mice.

  • IgG-switched memory B cells in IL6 knock-in mice displayed a diverse antibody repertoire and high specificity against immunized antigen.

Abstract

Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human IL6 gene encoding the cytokine that is important for B and T cell differentiation was knocked into its respective mouse locus. The provision of human IL6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum IgG. In addition, immunization with ovalbumin induced OVA-specific B cells only in human IL-6 knock-in mice. These OVA-specific antibodies displayed the highest frequency of somatic mutation, further suggesting that human IL-6 is important for efficient B cell activation and selection. We conclude that human IL6 knock-in mice represent a novel and improved model for human adaptive immunity without relying on complex surgery to transplant human fetal thymus and liver. These mice can therefore be used to exploit or evaluate immunization regimes that would be unethical or untenable in humans.

  • Submitted April 19, 2016.
  • Accepted December 21, 2016.