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

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.