A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR + cells during antibody‐mediated immune responses

Anna Louisa Thaller (1) , Friederike Jönsson (2) , Oriane Fiquet (1) , Solenne Marie (1) , Jean‐marc Doisne (1) , Giulia Girelli-Zubani (1) , Toshiki Eri (1) , Priyanka Fernandes (1) , Evgeny Tatirovsky (1) , Francina Langa Vives (3) , Pierre Bruhns (2) , Hélène Strick-Marchand (1) , James Di Santo (1)

1 Immunité Innée - Innate Immunity
2 Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology
3 CIGM - Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center

Human immune system (HIS) mice provide a model to study human immune responses in vivo. Currently available HIS mouse models may harbor mouse Fc Receptor (FcR)‐expressing cells that exert potent effector functions following administration of human Ig. Previous studies showed that the ablation of the murine FcR gamma chain (FcR‐γ) results in loss of antibody‐dependent cellular cytotoxicity and antibody‐dependent cellular phagocytosis in vivo. We created a new FcR‐γ‐deficient HIS mouse model to compare host (mouse) versus graft (human) effects underlying antibody‐mediated immune responses in vivo. FcR‐γ‐deficient HIS recipients lack expression and function of mouse activating FcRs and can be stably and robustly reconstituted with human immune cells. By screening blood B‐cell depletion by rituximab Ig variants, we found that human FcγRs‐mediated IgG1 effects, whereas mouse activating FcγRs were dominant in IgG4 effects. Complement played a role as an IgG1 variant (IgG1 K322A) lacking complement binding activity was largely ineffective. Finally, we provide evidence that FcγRIIIA on human NK cells could mediate complement‐independent B‐cell depletion by IgG1 K322A. We anticipate that our FcR‐γ‐deficient HIS model will help clarify mechanisms of action of exogenous administered human antibodies in vivo.

Mots clés: ADCC; NK cells; Antibody-mediated immune responses; Fc receptors; Human immune system (HIS) mice

Domaines: Sciences du Vivant [q-bio]

Anna Louisa Thaller, Friederike Jönsson, Oriane Fiquet, Solenne Marie, Jean‐marc Doisne, et al.. A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR + cells during antibody‐mediated immune responses. European Journal of Immunology, In press, ⟨10.1002/eji.202350454⟩. ⟨pasteur-04225194⟩