TCR activation induces ZIP8 expression in human T cells. This zinc accumulation inhibits tyrosine phosphatase SHP-1 recruitment for the negative regulation of TCR signaling, leading to the activation of the TCR-LCK-ZAP70 pathway for cell proliferation and cytokine production. When TCR signaling is activated by DCs, the ZIP6-mediated zinc level at spatially restricted regions near the immunological synapse between T cell and DC is increased.
TCR activation induces naïve CD4 T cells to differentiate into several T cell subsets including Th1, Th2, Th17, and Treg cells. CD4 T cells express the T cell receptor (TCR) on their surface, which recognizes antigenic peptides bound to MHC- α in DCs or other antigen presenting cells. CD4 T cells are white blood cells that mature in the thymus from thymocytes and play a central role in humoral immunity. ZIP6 is also an important molecule in CD4 T cells. Similar to LPS, the zinc-chelating reagent, TPEN ( N, N, N, N -tetrakis (2-pyridylmethyl)-ethylenediamine), induces a significant upregulation of the surface expression of the major histocompatibility complex (MHC) class II and CD86, leading to DC maturation.
LPS stimulation activates the TLR4-TRIF axis, resulting in downregulation of zinc importers ZIP6 and ZIP10 and upregulation of zinc exporters Znt1 and Znt6. When DCs are exposed to lipopolysaccharides (LPS), a ligand for toll-like receptor 4 (TLR4) is fragmented from the outer membrane of gram-negative bacteria, and intracellular zinc level is drastically decreased for maturation. Dendritic cells (DCs) that are differentiated from hematopoietic bone marrow progenitor cells play important roles in presenting antigens to T cells as messengers between the innate and the adaptive immune systems. ZIP6 and ZIP10 were initially reported as the key mammalian zinc transporters in the regulation of immune cell function. Two types of zinc transporters are conserved in mammals: Zrt-/Irt-like protein (ZIP) zinc transporters, which increase cytoplasmic zinc level by zinc import, and ZnTs (zinc transporters), which decrease cytoplasmic zinc level by zinc export. Zinc plays critical roles in the immune system, and its transport proteins, called zinc transporters, are reportedly involved in many immune responses. The Role of Zinc Transporters in Immune Cells
MEMBERS ONLY VOL 2 ZIP ZIP
A precise, comprehensive understanding of the structures and transport mechanisms of ZIP and ZnT in combination with mice experiments would provide promising drug targets as well as a basis for identifying other transporters with therapeutic potential. They show a unique architecture characterized by a Y-shaped conformation and a large cytoplasmic domain. Second, ZnT (zinc transporter) was initially identified in early studies of zinc biology it mediates zinc efflux as a counterpart of ZIPs in zinc homeostasis. Several ZIP members show specific extracellular domains composed of two subdomains, a helix-rich domain and proline-alanine-leucine (PAL) motif-containing domain. They form a homo- or heterodimer with 8 transmembrane domains and extra-/intracellular domains of various lengths. There are 14 ZIP family members in humans. First, Zrt-/Irt-like proteins (ZIPs) mediate the zinc influx from the extracellular or luminal side into the cytoplasm. In this review, we discuss the function, structure, and transport aspects of two major mammalian zinc transporter types, importers and exporters.
Recent advances have revealed the structural and biochemical bases for zinc transport across the cell membrane, with clinical implications for the regulation of zinc homeostasis in immune cells like dendritic cells, T cells, B cells, and mast cells. Zinc is an important trace metal in immune systems, and zinc transporters are involved in many immune responses.