| Abstract: | The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell–dependent and –independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.The humoral immune response is a major arm of the adaptive immune systems, in which B cells play a key role (1, 2). In the bone marrow (BM), the initial commitment to pro-B cells occurs, followed by their differentiation into pre-B cells and then into immature (IMM) B cells, which express the B-cell antigen receptor (BCR) on their surface. The IMM B cells then migrate to the spleen as transitional B cells, and further differentiate into follicular (FO) or marginal zone (MZ) mature B cells. FO B cells are a highly recirculating population, and are essential for T-cell–dependent (TD) immune responses, in which BCR-activated B cells enter the germinal center (GC), where they undergo massive expansion and Ig class-switch recombination (CSR). In contrast, MZ B cells are noncirculating and mediate rapid T-cell–independent (TI) immune responses against blood-borne pathogens. In addition to the conventional B-2 cell subset described above, a distinct B-1 cell subset resides mainly in the peritoneal cavity and produces natural antibodies (1, 2).The BCR is composed of membrane-bound Ig and associated Igα and Igβ subunits. Following BCR binding to its cognate antigen, the Igα and Igβ subunits are phosphorylated on tyrosines within their immunoreceptor tyrosine-based activation motifs (ITAMs) by SRC family kinases, including LYN (3). The SYK tyrosine kinase is then recruited to the phosphorylated ITAMs, resulting in SYK’s activation, and the subsequent activation of downstream molecules, such as ERK, PI3K, and NF-κB. BCR activation not only drives adaptive immune responses, but also mediates a “tonic” signal together with B-cell–activating factor (BAFF) receptor (BAFFR) signaling to help maintain immunocompetent mature B-cell pools in the steady state (4, 5). Thus, BCR signaling critically regulates the activation status and fate decisions of B cells.Zinc (Zn) deficiency leads to lymphopenia and to attenuations of both cellular and humoral immunity, resulting in an increased susceptibility to various pathogens (6, 7). Zn is reported to function as a signaling factor (8–11) and its homeostasis is tightly controlled by Zn transporters, the SLC39/ZIP and SLC30/ZnT family members, which contribute to Zn influx and efflux, respectively (12, 13). Notably, it was shown that Zn transferred by a specific Zn transporter can selectively fine-tune distinct intracellular signaling events (14) by targeting specific signaling molecules (15–20). Moreover, the disruption of a given Zn signaling axis can have pathogenic consequences in the absence of redundant machinery (21). However, the specific mechanisms involved in Zn and Zn transporter modulation of the immune system—in particular, the humoral immune response—are not well understood.In this study, we showed that the Zn transporter, ZIP10 (Zrt- and Irt-like protein 10), is required for proper antibody responses following BCR activation. Mice with a conditional knockout of ZIP10 in mature B cells showed dramatic attenuations of TD and TI antibody responses. In addition, GC development failed in these mice, resulting in a marked reduction in antigen-specific IgG1 responses. Moreover, ZIP10 deficiency led to hyperactivated BCR signaling, which reduced cell proliferation because of decreased CD45R protein tyrosine phosphatase (PTPase) activity. Our results establish a link between ZIP10 and humoral immunity, in which ZIP10 controls the BCR signal strength as a positive regulator of CD45R, thereby setting a threshold for B-cell signaling. |
