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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. [ABSTRACT FROM AUTHOR]

T cell lymphopenia results in peripheral homeostatic expansion to maintain the T cell immune system, which is termed lymphopenia-induced proliferation (LIP). LIP is a potential risk for expanding autoreactive clones to become pathogenic in human and murine autoimmune diseases. However, the ontogeny of T cells that induce autoantibody production by autoreactive B cells in LIP remains unclear. Transfer of CD4+CD25− conventional T (Tc) cells into T-cell-deficient athymic nude mice has been previously reported as a LIP-induced autoimmune model which develops organ-specific autoimmune diseases and systemic antinuclear antibodies (ANAs). We show here that via LIP in this model, Tc cells proliferated and differentiated into PD-1+CXCR5−/dim B-helper T cells, which promoted splenic germinal center (GC) formation, provided help for autoantibody-producing B cells, and had distinctive features of follicular helper T (Tfh) cells except that they do not express high CXCR5. Intestinal microbiota were essential for their generation, since depletion of them in recipient mice by antibiotics resulted in a reduction of LIP-induced PD-1+CXCR5−/dim B-helper T cells and an amelioration of autoimmune responses. Our findings will contribute to the elucidation of the mechanism of lymphopenia-induced autoimmunity and autoantibody production, and will pave the way for microbiota-targeted novel therapeutic approaches to systemic autoimmune diseases. [ABSTRACT FROM AUTHOR]

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., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

T cell lymphopenia results in peripheral homeostatic expansion to maintain the T cell immune system, which is termed lymphopenia-induced proliferation (LIP). LIP is a potential risk for expanding autoreactive clones to become pathogenic in human and murine autoimmune diseases. However, the ontogeny of T cells that induce autoantibody production by autoreactive B cells in LIP remains unclear. Transfer of CD4 + CD25 - conventional T (Tc) cells into T-cell-deficient athymic nude mice has been previously reported as a LIP-induced autoimmune model which develops organ-specific autoimmune diseases and systemic antinuclear antibodies (ANAs). We show here that via LIP in this model, Tc cells proliferated and differentiated into PD-1 + CXCR5 -/dim B-helper T cells, which promoted splenic germinal center (GC) formation, provided help for autoantibody-producing B cells, and had distinctive features of follicular helper T (Tfh) cells except that they do not express high CXCR5. Intestinal microbiota were essential for their generation, since depletion of them in recipient mice by antibiotics resulted in a reduction of LIP-induced PD-1 + CXCR5 -/dim B-helper T cells and an amelioration of autoimmune responses. Our findings will contribute to the elucidation of the mechanism of lymphopenia-induced autoimmunity and autoantibody production, and will pave the way for microbiota-targeted novel therapeutic approaches to systemic autoimmune diseases.