B-cell receptor strength and zinc signaling: Unraveling the role of zinc transporter ZIP10 in humoral immunity

The humoral immune response, alongside cell-mediated immunity, in which B cells play a key role, form the primary arms of the adaptive immune system. Resting mature follicular (FO) B cells in the spleen are essential for antibody-mediated immune responses. They recirculate through the blood, and are activated upon the binding of various diverse cognate antigens to the specific B cell antigen receptor (BCR) on their cell surface. With the help of T cells, the activated FO B cells undergo the germinal center (GC) reaction, which involves massive expansion and immunoglobulin (Ig) class-switch recombination (e.g. IgM to IgG1) to elicit a high-affinity antibody response against the antigens. Zinc (Zn) is essential in immunity, and in both humans and rodents, aberrant Zn homeostasis strongly disrupts the cellularity and functions of immune cells, leading to thymic and splenic atrophy, lymphopenia, and weakened cellular and humoral immunity, which increases the host’s susceptibility to various pathogens. Zn, which is transported by specific members of the Zn-transporter families, SLC39/ZIP and SLC30/ZnT, selectively fine-tunes distinct intracellular signaling events by targeting signaling molecules involved in development, growth, and immunity. Zn controls a wide range of immune signaling cascades that lead to cytokine production, antigen presentation, and the activation of kinases and transcription factors in immune cells, and disrupting the specific Zn transporter−Zn signal axis impairs cellular function. However, how Zn controls immune function, in particular the humoral immune response, is poorly understood. In this research highlight, we review our recent finding that ZIP10-Zn signaling is required in B-cell receptor signaling for the antibody-mediated immune response.