Ca signals are essential for T-cell proliferation, while Zn 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) and zinc (Zn) 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- and Ca 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-deficient patients. Human peripheral blood mononuclear cells were stimulated with the Zn ionophore pyrithione and thapsigargin, an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca ATPase (SERCA). Intracellular Zn and Ca 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 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 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 and Ca 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 and Zn 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.