T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions.
The trace element zinc is a crucial cofactor for many proteins involved in cellular processes like differentiation, proliferation and apoptosis. Zinc homeostasis is tightly regulated and disturbance of this homeostasis due to genetic defects, zinc deficiency, or supplementation influences the development and the progression of various infectious and autoimmune diseases. The immune system is strongly impaired during zinc deficiency, predominantly the cell-mediated response by T-lymphocytes. During zinc deprivation T-lymphocyte development, polarization into effector cells, and function are impaired. This leads to reduced T-cell numbers, a decreased ratio of type 1 to type 2 T-helper cells with reduced production of T-helper type 1 cytokines like interferon-gamma, and compromised T-cell mediated immune defense. Accordingly, disturbed zinc homeostasis increases the risk for infections, and zinc supplementation restores normal immune function. Furthermore, several disorders, like mycobacterial infections, asthma, diabetes, and rheumatoid arthritis are accompanied by decreased zinc levels and in some cases disease progression can be affected by zinc supplementation. On the molecular level, apoptosis of T-cell precursors is influenced by zinc via the Bcl-2/Bax ratio, and zinc ions inhibit caspases-3, -6, -7, and -8. In mature T-cells, zinc interacts with kinases involved in T-cell activation, like protein kinase C and the lymphocyte protein tyrosine kinase (Lck), while higher zinc concentrations are inhibitory, reducing the activities of the interleukin-1 receptor-associated kinase (IRAK) and calcineurin. Taken together, zinc homeostasis influences T-lymphocytes via several molecular targets, leading to a modulation of T-cell-dependent immune responses.
Hönscheid
Andrea
A
Institute of Immunology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany.
Rink
Lothar
L
Haase
Hajo
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D065095:Calcineurin Inhibitors; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D015032:Zinc / Q000172:deficiency / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D053592:Interleukin-1 Receptor-Associated Kinases; D011493:Protein Kinase C; D015032:Zinc