bims-hummad 2026-07-05 papers

Exp Mol Med. 2026 Jul 03.

Establishing human immune system mice: application, opportunity, and challenges.

Pei-Chuan Chiang, Hung Lee-Chan, Yungling Leo Lee.

Human immune system (HIS) models offer a promising solution to bridge clinical trial by providing a more functional platform in studying disease mechanisms and evaluating therapeutic responses. This Review provides an overview of various strains of immunodeficient mice used for human immune cell development and their current applications in disease modeling. We highlight the utility of single-cell RNA sequencing in HIS mice as a powerful approach for identifying drug targets and elucidating cellular mechanisms. Furthermore, we discuss four major challenges in HIS model establishment and summarize recent advancements aimed at enhancing human immune cell development. Finally, we present preclinical examples of HIS mice as disease platforms supporting clinical trials, illustrating their role as essential tools for drug development.

DOI: https://doi.org/10.1038/s12276-026-01777-1

Front Immunol. 2026 ;17 1734493

Targeted replacement of human γδ TCR in mice enhances antigen-specific B cell immunity.

Husheem Michael, Michael Pitre, Gene W Weng, Mikaela M Vallas, Ellen Chen, Paul Sheiffele, Wei Weng.

The humanized (Hu) gamma delta (γδ) T cell receptor (TCR) -T1 (γδ HuTCR-T1) mouse model represents a novel and versatile platform for investigating human-like immune responses in vivo. In this study, we assessed the adaptive and humoral immune responses of γδ HuTCR-T1 mice compared with wild-type (WT) counterparts following immunization with collagen and keratin antigens. γδ HuTCR-T1 mice exhibited markedly enhanced B cell activity, as demonstrated by a significant increase in antigen-specific antibody-secreting cells (ASCs), elevated serum titers of antigen-specific IgG, IgA, and IgE, and expansion of both plasma and memory B cell populations within spleen and blood tissues. In addition to the amplified B cell responses, γδ HuTCR-T1 mice displayed a distinct and dynamic cytokine profile, characterized by increased production of interleukin (IL)-4, IL-6, IL-10, IL-17, TGFβ, IFNγ, and TNFα, reflecting a balanced pro- and anti-inflammatory immune landscape. Importantly, serum levels of anti-ANA antibodies remained below the detection threshold. Collectively, these findings demonstrate that human γδ T cells modulate adaptive and humoral immunity through both direct cellular interactions and cytokine-driven mechanisms that promote B cell maturation, activation, and class switching. This work advances our understanding of γδ T cells as critical regulators of immune homeostasis and highlights the γδ HuTCR-T1 model as a valuable translational resource for preclinical studies.

Keywords: B cells; antibody production; antibody secreting plasma B cell; humanized γδ TCR mice; immunization

DOI: https://doi.org/10.3389/fimmu.2026.1734493

Front Immunol. 2026 ;17 1796692

HLA-DRB1*15:01 drives sex- and age-dependent microglial immune phenotypes and neuroimmune signaling.

Elsa M Reyes-Reyes, Dhanalakshmi Chinnasamy, Michael D Trial, Fernando Fernandez, Vincent D Nguyen, Qianying He, Angel-Grace Leslie, Jessica Begay, Jessica Triplett, David Bradford, Carolina Figueroa, Jean P Wiegand, Kathleen E Rodgers.

Introduction: The major histocompatibility complex class II (MHC-II) pathway is central to adaptive immunity and immune tolerance, and its age-related dysregulation is increasingly linked to chronic neuroinflammation. The HLA-DRB1*15:01 allele, the strongest genetic risk factor for multiple sclerosis, has been implicated in shaping pathogenic CD4+ T-cell responses and broader neuroimmune vulnerability, yet how this allele modulates age- and sex-dependent neuroimmune processes within the central nervous system (CNS) remains poorly defined.
Methods: We investigated the impact of HLA-DRB1*15:01 expression using a humanized mouse model (HLA mice) and wild-type (WT) controls. Male and female mice were analyzed at 6, 9, and 15 months of age, with endocrine stratification in females. Behavioral testing, flow cytometry, immunofluorescence, and multiplex cytokine analyses were used to assess cognitive performance, glial immune-associated changes and oxidative stress, astrocyte-microglia IL-3/IL-3R signaling, endothelial activation, selective immune cell accumulation at CNS borders, tissue organization, and hippocampal cytokine profiles.
Results: HLA mice developed age- and sex-dependent cognitive impairment, most pronounced in aged females. HLA-DRB1*15:01 expression promoted progressive microglial immune-associated changes, characterized by increased CD14 and CD68 expression, elevated mitochondrial oxidative stress, altered astrocyte phenotypes, and enhanced IL-3/IL-3R signaling. Hippocampal axonal and myelin organization was disrupted in aged HLA mice and was spatially associated with increased microglial presence. HLA mice also exhibited selective immune remodeling, including increased accumulation of CD4+ T cells and NK1.1+CD3+ natural killer T (NKT) cells, particularly in females, accompanied by endothelial activation marked by elevated ICAM-1 and E-selectin expression. Hippocampal cytokine profiling revealed selective sex-biased alterations, without broad induction of classical inflammatory cytokines.
Conclusion: Together, these findings demonstrate that HLA-DRB1*15:01 drives a coordinated, age- and sex-dependent neuroinflammatory program linking behavioral dysfunction, glial immune-associated changes and oxidative stress, selective immune cell recruitment, endothelial activation, tissue remodeling, and targeted cytokine imbalance. This integrated phenotype provides mechanistic insight into how this major MS risk allele confers vulnerability to chronic neuroinflammation during aging, with heightened impact in females, independent of reproductive cycling stage.

Keywords: HLA-DRB1*15:01; aging; microglial activation; neuroimmune signaling; neuroinflammation; sex differences

DOI: https://doi.org/10.3389/fimmu.2026.1796692

Microbiome. 2026 Jun 29. pii: 176. [Epub ahead of print]14(1):

IL-17A deficiency in HLA-DR3 transgenic mice enriches beneficial Prevotella species in gut to promote Tregs and reduce CNS autoimmunity.

Shailesh K Shahi, Sudeep Ghimire, Samantha N Jensen, Peter C Lehman, Allison G Rux, Souradip Sinha, Nicholas Borcherding, Munir R Tanas, Katherine N Gibson-Corley, Sukirth M Ganesan, Nitin J Karandikar, Ashutosh K Mangalam.

BACKGROUND: Human Leukocyte Antigen (HLA) class-II genes, particularly HLA-DR2 and HLA-DR3, and the gut microbiota are intricately linked to the pathobiology of multiple sclerosis (MS) through their ability to regulate host immunity, a critical factor in disease pathogenesis. An imbalance between anti-inflammatory CD4+ Tregs and pro-inflammatory IL-17A-secreting CD4+ Th17 cells is thought to drive disease. However, a key unresolved question is whether HLA-class II-restricted CD4+IL-17A cells can influence Treg populations and the extent to which gut microbiota regulate this IL-17A-Treg axis. Therefore, we utilized humanized transgenic mice expressing the HLA class-II gene and deficient in mouse class-II molecules, where all CD4+ T cells are selected on the human HLA class-II molecule, closely mimicking human immune responses.
RESULTS: Utilizing IL-17A-deficient (DR3.IL-17A-/-) mice expressing HLA-DR3 (HLA-DRβ1*0301), we show that IL-17A deficiency enriches beneficial gut bacteria, including Prevotella species, enhances peroxisome proliferator-activated receptor (PPAR) signaling, and increases FoxP3+ regulatory T (Treg) cells and IL-10 production. The importance of gut microbiota in promoting Tregs and anti-inflammatory responses was confirmed by administering Prevotella copri, a common commensal in human gut, which mirrored the effects observed in IL-17A-deficient mice by inducing PPAR signaling and Treg population. Moreover, DR3.IL-17A-/- mice exhibited a marked reduction in EAE severity compared to IL-17A-sufficient (DR3) mice, underscoring the enhanced functional capacity of the Treg population in mitigating disease progression. Cohousing experiments validated the role of gut microbiota in immune regulation including Treg induction, as demonstrated by the transfer of Prevotella species from IL-17A-deficient mice to IL-17A-sufficient mice, increased Treg populations and attenuated EAE severity in recipient DR3 mice.
CONCLUSIONS: This study redefines IL-17A's role in immune regulation, emphasizing its ability to directly influence gut microbiota composition and the abundance of Treg-promoting bacteria. Thus, gut microbiota-targeted therapies, particularly those promoting Treg-inducing bacteria like Prevotella species, hold promise for treating autoimmune diseases by modulating host immune responses. Video Abstract.

Keywords: Prevotella ; Experimental Autoimmune Encephalomyelitis (EAE); Gut microbiota; IL-17A; Immune regulation; Multiple sclerosis; Tregs

DOI: https://doi.org/10.1186/s40168-026-02394-w