Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as “zinc waves”, and late homeostatic zinc signals regarding prolonged changes in intracellular zinc.

During the last few decades, the micronutrient zinc has proven to be an important metal ion for a well-functioning immune system, and thus also for a suitable immune defense. Nowadays, it is known that the main cause of zinc deficiency is malnutrition. In particular, vulnerable populations, such as the elderly in Western countries and children in developing countries, are often affected. However, sufficient zinc intake and homeostasis is essential for a healthy life, as it is known that zinc deficiency is associated with a multitude of immune disorders such as metabolic and chronic diseases, as well as infectious diseases such as respiratory infections, malaria, HIV, or tuberculosis. Moreover, the modulation of the proinflammatory immune response and oxidative stress is well described. The anti-inflammatory and antioxidant properties of zinc have been known for a long time, but are not comprehensively researched and understood yet. Therefore, this review highlights the current molecular mechanisms underlying the development of a pro-/ and anti-inflammatory immune response as a result of zinc deficiency and zinc supplementation. Additionally, we emphasize the potential of zinc as a preventive and therapeutic agent, alone or in combination with other strategies, that could ameliorate infectious diseases.

In recent decades, it has become clear that allergic diseases are on the rise in both Western and developing countries. The exact reason for the increase in prevalence has not been conclusively clarified yet. Multidimensional approaches are suspected in which diet and nutrition seem to play a particularly important role. Allergic diseases are characterized by a hyper-reactive immune system to usually harmless allergens, leading to chronic inflammatory diseases comprising respiratory diseases like asthma and allergic rhinitis (AR), allergic skin diseases like atopic dermatitis (AD), and food allergies. There is evidence that diet can have a positive or negative influence on both the development and severity of allergic diseases. In particular, the intake of the essential trace element zinc plays a very important role in modulating the immune response, which was first demonstrated around 60 years ago. The most prevalent type I allergies are mainly based on altered immunoglobulin (Ig)E and T helper (Th)2 cytokine production, leading to type 2 inflammation. This immune status can also be observed during zinc deficiency and can be positively influenced by zinc supplementation. The underlying immunological mechanisms are very complex and multidimensional. Since zinc supplements vary in dose and bioavailability, and clinical trials often differ in design and structure, different results can be observed. Therefore, different results are not surprising. However, the current literature suggests a link between zinc deficiency and the development of allergies, and shows positive effects of zinc supplementation on modulating the immune system and reducing allergic symptoms, which are discussed in more detail in this review.

The intracellular free zinc level and zinc distribution are important for cellular function. Both are highly variable and are altered due to intrinsic zinc pool fluctuation via buffering and muffling reactions. Multiple autoimmune diseases are associated with pathologically changed zinc levels, which provoke altered signal transduction leading to changed immune responses, cell differentiation, and function. For instance, immunological tolerance can be impaired, causing autoimmune diseases because of a malfunction of regulatory T cells (Tregs). We investigated the intracellular free zinc concentration of resting and activated T helper (Th) cells and Tregs in an allogeneic graft versus host disease model using fluorescence-activated cell sorting (FACS) analysis and enlightened cell function under nontoxic zinc concentrations and zinc deficiency by detecting cytokine secretion via enzyme-linked immunosorbent assay (ELISA). We exhibited for the first time that Tregs could be explicitly discriminated from other Th cell subsets using significantly increased intracellular free zinc levels. Moreover, the intracellular free zinc level was essential in maintaining the Treg phenotype and function, since zinc deficiency favored the pro-inflammatory immune response. Therefore, we hypothesize that the intracellular free zinc level in Th cells is essential in guaranteeing proper cellular function and can be used to discriminate Tregs from other Th cell subsets.

Nutrition is a key determinant of health and may be regarded as a form of preventive medicine, as an adequate supply of vitamins, fats, proteins, and trace elements is essential for proper immune function. In recent decades vegetarian and vegan diets have become increasingly popular but may increase the risk of trace element deficiencies if not carefully planned. Zinc deficiency can impair immune responses and reduce resistance to infections. While previous research has mainly focused on animal models or elderly populations, little is known about younger adults. Thus, we investigated the impact of zinc intake through different diets (omnivorous, vegetarian, and vegan) on immune function in healthy young volunteers aged 19 to 33 years. We identified zinc deficiency to be prominent in young, healthy individuals adhering to plant-based diets (vegetarian and vegan) compared with omnivorous individuals of the same age. This was associated with impaired immune function, as indicated by reduced IL-2 cytokine production, which was linked to zinc deficiency-depended overexpression of CREMα. Furthermore, we validated the applicability of our recently established food frequency questionnaire (FFQ) in this cohort. Individuals adhering to plant-based diets are at considerable risk of developing zinc deficiency. Zinc deficiency, regardless of diet, provokes immune system dysfunction by impairing IL-2 production, a consequence of zinc deficiency-dependent overexpression of CREMα. These results underscore the critical importance of ensuring adequate zinc intake among young individuals following plant-based diets to prevent severe immune dysfunction.