Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3

Abstract

• Improved adaptive immune responses in humanized mice lacking murine MHC II and expressing human HLADR1.• NOD.Prkdc H2-Ab1 2/2Tg(HLA-DR1) mice reconstituted with hematopoietic stem cells from an IPEX syndrome patient develop fatal autoimmunity.Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics. (Blood. 2015;125(25):3886-3895)

AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice

“…Although sub-optimal adaptive immune responses are often observed in many humanized murine systems, we recently described NOD. Prkdc scid .Il2rg −/− (NSG) mice that lack murine major histocompatibility complex (MHC) class II and instead express human leukocyte angtigen-DR1 (HLA-DR1) under the control of the murine MHC class II promoter (NSGAb o DR1 mice) (Goettel et al, 2015). These mice intrinsically lack murine lymphocytes as well as NK cells and when made immune replete using human CD34 + hematopoietic stem cells (HSCs) the mice displayed improved human CD4 + T cell responses (Goettel et al, 2015).…”

“…Prkdc scid .Il2rg −/− (NSG) mice that lack murine major histocompatibility complex (MHC) class II and instead express human leukocyte angtigen-DR1 (HLA-DR1) under the control of the murine MHC class II promoter (NSGAb o DR1 mice) (Goettel et al, 2015). These mice intrinsically lack murine lymphocytes as well as NK cells and when made immune replete using human CD34 + hematopoietic stem cells (HSCs) the mice displayed improved human CD4 + T cell responses (Goettel et al, 2015). In order to specifically evaluate CD4 + T cell responses, we used a reductionist approach by reconstituting NSGAb o DR1 mice with human CD4 + T cells isolated from allelically-matched HLA-DR1 + donors.…”

“…We recently described improved human T cell responses in NSGAb o DR1 mice that express human, but not murine, MHC class II. Moreover, when these mice were reconstituted using HSCs isolated from an IPEX patient lacking functional FOXP3 and Tregs (Goettel et al, 2015), the mice developed a multi-organ inflammatory syndrome with the development of autoantibodies analogous to patients. We expanded upon this model and demonstrated that in the presence of normal human T cells, TNBS administration to NSGAb o DR1 mice resulted in severe intestinal inflammation.…”

Differential effect of HLA class-I versus class-II transgenes on human T and B cell reconstitution and function in NRG mice

“…The NRG and NSG mice carry a full deletion of the IL2Rγc gene3, whereas the NOG mice have a partial deletion of the IL2R g c gene30, though both mutations have been proven to equally prevent the development of mouse innate cells (particularly mouse NK cells). Besides these genetic differences, there is consensus on the ability of HLA class II expressing NRG, NOG, and NSG mice (infused with HSC from cord blood) to improve reconstitution of human CD4 T cells121314. In contrast, there is one study in NSG mice co-expressing HLA-DR1 and HLA-A2 transgenes (infused with HSC from fetal liver) which showed no improvement in the numbers of reconstituted human CD4 T cells as compared to non-Tg NSG mice15 (Table 1).…”

HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

“…By reconstituting immunodeficient mice with bone marrow (BM)-derived HSCs from adults with established disease, we aimed to identify HSC-intrinsic abnormalities in immune regulation and development because some autoimmune diseases are transferable by HSCs. [11][12][13][14][15][16] Therefore, underlying immunoregulatory defects could potentially be dissected in this model.…”