Ca 2+ signals are essential for T-cell proliferation, while Zn 2+ signals are necessary for T helper cell 1 differentiation.

The regulation of T-cell fate is crucial for the balance between infection control and tolerance. Calcium (Ca 2+ ) and zinc (Zn 2+ ) signals are both induced after T-cell stimulation, but their specific roles in the fate of activation and differentiation remain to be elucidated. Are Zn 2+ - and Ca 2+ signals responsible for different aspects in T-cell activation and differentiation and do they act in concert or in opposition? It is crucial to understand the interplay of the intracellular signals to influence the fate of T cells in diseases with undesirable T-cell activities or in Zn 2+ -deficient patients. Human peripheral blood mononuclear cells were stimulated with the Zn 2+ ionophore pyrithione and thapsigargin, an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase (SERCA). Intracellular Zn 2+ and Ca 2+ signals were monitored by flow cytometry and ELISA, quantitative PCR and western blot were used to evaluate T-cell differentiation and the underlying molecular mechanism. We found that Zn 2+ signals upregulated the early T-cell activation marker CD69, interferon regulatory factor 1 (IRF-1), and Krüppel-like factor 10 (KLF-10) expression, which are important for T helper cell (Th) 1 differentiation. Ca 2+ signals, on the other hand, increased T-bet and Forkhead box P3 (FoxP3) expression and interleukin (IL)-2 release. Most interestingly, the combination of Zn 2+ and Ca 2+ signals was indispensable to induce interferon (IFN)-γ expression and increased the surface expression of CD69 by several-fold. These results highlight the importance of the parallel occurrence of Ca 2+ and Zn 2+ signals. Both signals act in concert and are required for the differentiation into Th1 cells, for the stabilization of regulatory T cells, and induces T-cell activation by several-fold. This provides further insight into the impaired immune functions of patients with zinc deficiency.