This study introduces a humanized mouse model, THX, which successfully replicates human immune responses. THX mice are generated by grafting genetically myeloablated Kit^W-41j mutant immunodeficient pups with human cord blood CD34+ cells, followed by 17β-estradiol conditioning to promote immune cell differentiation. These mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells, and neutrophils. They develop well-formed lymph nodes and intestinal lymphoid tissue, including Peyer's patches, and human thymic epithelial cells. THX mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses, involving somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon vaccination with flagellin or a Pfizer-BioNTech coronavirus disease 2019 (COVID-19) mRNA vaccine, THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain, with blood incretion of human cytokines, including APRIL, BAFF, TGF-β, IL-4, and IFN-γ, at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses, THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics. THX mice support full and sustained development of human immune cells, with a human-like intestinal microbiome. They have a T cell-dependent and T cell-independent antibody response, with high-affinity antibodies and memory B cells. THX mice can model SLE autoimmunity, showing a malar rash, antinuclear antibodies, and kidney immunopathology. The study highlights the importance of estrogen conditioning in the development of THX mice, which enables the full maturation of human immune responses. This model represents a significant advancement in humanized mouse models, offering a more accurate representation of human immunity for research and therapeutic development.This study introduces a humanized mouse model, THX, which successfully replicates human immune responses. THX mice are generated by grafting genetically myeloablated Kit^W-41j mutant immunodeficient pups with human cord blood CD34+ cells, followed by 17β-estradiol conditioning to promote immune cell differentiation. These mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells, and neutrophils. They develop well-formed lymph nodes and intestinal lymphoid tissue, including Peyer's patches, and human thymic epithelial cells. THX mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses, involving somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon vaccination with flagellin or a Pfizer-BioNTech coronavirus disease 2019 (COVID-19) mRNA vaccine, THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain, with blood incretion of human cytokines, including APRIL, BAFF, TGF-β, IL-4, and IFN-γ, at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses, THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics. THX mice support full and sustained development of human immune cells, with a human-like intestinal microbiome. They have a T cell-dependent and T cell-independent antibody response, with high-affinity antibodies and memory B cells. THX mice can model SLE autoimmunity, showing a malar rash, antinuclear antibodies, and kidney immunopathology. The study highlights the importance of estrogen conditioning in the development of THX mice, which enables the full maturation of human immune responses. This model represents a significant advancement in humanized mouse models, offering a more accurate representation of human immunity for research and therapeutic development.