Archives of Biochemistry and Biophysics 611 (2016) 58e65

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Archives of Biochemistry and Biophysics

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Zinc and immunity: An essential interrelation

Maria Maares, Hajo Haase*
Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The significance of the essential trace element zinc for immune function has been known for several
Received 1 February 2016 decades. Zinc deficiency affects immune cells, resulting in altered host defense, increased risk of
Received in revised form inflammation, and even death. The micronutrient zinc is important for maintenance and development of
16 March 2016
immune cells of both the innate and adaptive immune system. A disrupted zinc homeostasis affects these
Accepted 23 March 2016
cells, leading to impaired formation, activation, and maturation of lymphocytes, disturbed intercellular
Available online 26 March 2016
communication via cytokines, and weakened innate host defense via phagocytosis and oxidative burst.
This review outlines the connection between zinc and immunity by giving a survey on the major roles of
Keywords:
Zinc
zinc in immune cell function, and their potential consequences in vivo.
Immune system © 2016 Elsevier Inc. All rights reserved.
Cytokines
Innate immunity
Adaptive immunity

1. Introduction results in a plateau of plasma zinc, with most studies averaging

Zinc plays an important role in the immune system, affecting
both innate and adaptive immune cells. This is highlighted by the
effects of zinc deficiency, including thymic atrophy, lymphopenia,
impaired cellular and antibody-mediated immune responses, and
even death [1,2]. Since the relationship between zinc deficiency and
immune dysfunction was discovered about 50 years ago, it has been
widely investigated [3]. The role of zinc in immune function, its
effects on immune cells, and the underlying molecular mechanisms
have been described [4,5], including its importance as a signaling
molecule [6e8]. Because zinc deficiency is closely linked to insuf-
ficient dietary intake or impaired resorption, especially people from
developing countries, elderly, vegetarians/vegans, and patients
with some chronic diseases, such as renal insufficiency and chronic
diarrhea, are affected [9e12]. Zinc supplementation can either
restore or even improve immune function [13e16] and has been
used as a therapeutic treatment in chronic gastrointestinal disor-
ders, renal diseases, and genetic predispositions, such as sickle cell
anemia and the zinc malabsorption syndrome acrodermatitis
enteropathica [11]. Physiological plasma zinc levels vary around
12e16 mM [17,18], providing an important pool for immune cells
[19]. In healthy individuals, substantial dietary zinc restriction
significantly decreases plasma levels, whereas elevated zinc intake
* Corresponding author.
E-mail address: Haase@TU-Berlin.de (H. Haase).
around a value of 14 mM [20].
A disrupted zinc homeostasis causes impaired immune func-
tion, leading to compromised host defense and an increased risk of
excessive inflammation. Deficiency and supplementation of this
essential micronutrient are important factors influencing the im-
mune system. Thus, the significance of zinc for selected innate and
adaptive immune cells is discussed below.
2. Innate immune system
Upon recognition of characteristic molecular patterns of path-
ogens, the innate immune system initiates an immediate immune
response, mainly maintained by neutrophil granulocytes, mono-
cytes, and macrophages. They directly attack pathogens, com-
plemented by natural killer cells, which recognize and kill virus-
infected and tumor cells [21,22]. Additionally, innate immune
cells release various cytokines and chemokines, soluble proteins
that are recognized by corresponding receptors on innate and
adaptive immune cells. These signals enable intercellular commu-
nication, which coordinates the immune response [23,24]. During
the acute phase of an infection, one systemic response that is co-
ordinated by cytokines leads to decreased concentrations of several
essential trace elements in the plasma, including zinc. This process
is known as nutritional immunity. Not only leukocytes, but also
pathogens critically depend on zinc, and withdrawal of nutrients
aims to hinder pathogenic growth [25,26].

http://dx.doi.org/10.1016/j.abb.2016.03.022
0003-9861/© 2016 Elsevier Inc. All rights reserved.
 M. Maares, H. Haase / Archives of Biochemistry and Biophysics 611 (2016) 58e65 59

Abbreviations NK natural killer cell

NKT natural killer T-cell
APC antigen presenting cell PBMC peripheral blood mononuclear cells
BCR B-cell receptor PDE cyclic nucleotide phosphodiesterases
cAMP cyclic adenosine monophosphate PKA protein kinase A
Con A Concanavalin A PKC protein kinase C
CD cluster of differentiation PMA phorbol-12-myristate 13-acetate
DC dendritic cells PMN polymorphonuclear leukocytes
EAE experimental autoimmune encephalomyelitis TH T helper cells
cGMP cyclic guanosine monophosphate T-bet T-box transcription factor
IL interleukin TCR T-cell receptor
IL-2Ra IL-2 receptor alpha chain TLR Toll-like receptor
IL-12Rb2 IL-12 receptor beta 2 subunit TNF-a tumor necrosis factor-a
IFN interferon TRIF toll/IL-1R domain-containing adapter inducing IFN-b
IRF3 IFN regulatory factor 3 TPEN N, N, N0 , N0 -tetrakis-[2-pyridylmethyl]-
KIR killer inhibitory receptors ethylenediamine
LPS lipopolysaccharide Treg regulatory T-cell
MHC major histocompatibility complex ZnT zinc transporter
MyD88 myeloid differentiation primary response gene 88 ZIP Zrt/Irt-like protein
NF-kB nuclear factor-kB

2.1. Polymorphonuclear leucocytes
After invasion of pathogens or inflammation, poly-
morphonuclear leukocytes (PMN) (also referred to as granulocytes)
migrate via adhesion and chemotaxis into the infected tissue as a
response to signals derived from the source of infection [27,28]. The
most abundant PMN are neutrophil granulocytes, alongside with
eosinophils and basophiles. They provide the first line of host de-
fense by phagocytosis, NETosis, degranulation and secretion of
several cytokines [27,29,30]. In addition to phagocytosis, oxidative
burst represents an important defense mechanism of activated
neutrophils. After internalization, granulocytes kill the pathogens
by generating reactive oxygen species (ROS), which is mainly
mediated by high NADPH oxidase activity [21,31]. Physiological zinc
concentrations were reported to be essential for ROS generation in
human leukocytes, whereas extremely high zinc concentrations
(10 mM) resulted in a strong decrease [32]. Moreover, zinc defi-
ciency was shown to increase the amount of ROS in vitro after in-
duction with phorbol-12-myristate-13-acetate (PMA) [33]. Zinc is a
known inhibitor of the NADPH oxidase [34], suggesting that zinc
deficiency might lead to enhanced NADPH oxidase activity, thereby
elevating ROS production. Yet, zinc has a multitude of other pro-
antioxidant functions [35,36], which may also be contributing to
elevated ROS levels during a shortage of zinc.
During zinc deficiency, impaired function of PMN in vivo was
reported, resulting in decreased activity, phagocytosis (Fig. 1) and
altered host defense [37,38]. Neutrophil granulocytes secrete
interleukin (IL)-8, a chemokine that attracts additional gran-
ulocytes and acts as a chemoattractant for T-cells. Additionally, they
release the anti-inflammatory IL-1 receptor antagonist (IL-1ra),
which highlights their role in regulation and resolution of the in-
flammatory response. Lipopolysaccharides (LPS) from the cell wall
of gram-negative bacteria induce the release of IL-8 and IL-1ra [39].
This is impaired by zinc deprivation, indicating the importance of
zinc for granulocyte function. Moreover, chemotaxis was observed
to be impaired by zinc deficiency and induced by high zinc con-
centrations (500 mM) in rat granulocytes in vitro, suggesting that
zinc itself acts as a chemoattractant [40]. However, others could not
reproduce this direct action of zinc in human leukocytes [39].
NETosis is the formation and release of neutrophil extracellular
traps (NETs). These NETs are composed of DNA, chromatin, and
granule proteins and released by PMNs to capture and kill extra-
cellular pathogens. Zinc signals are involved in the formation of
NETs. Compared to untreated control cells, decreased NETosis was
observed in PMN in vitro after zinc chelation by the chelator N, N,
N0 , N0 -tetrakis-[2-pyridylmethyl]-ethylenediamine (TPEN), because
the ROS-dependent signal transduction cascade that leads to
NETosis requires zinc signals [31]. Taken together, sufficient supply
of zinc enables regular function of neutrophil granulocytes,
whereas either zinc deprivation or excess impair their activity.
2.2. Monocytes and macrophages
Monocytes represent another important cell type of innate
immunity. They migrate into the infected tissue shortly after the
PMN, where they differentiate into macrophages. Alongside with
PMN, they mediate host defense via phagocytosis and oxidative
burst. In addition, they are antigen presenting cells (APCs) and
secrete pro-inflammatory cytokines to regulate the immune
response [21,41]. During in vitro zinc deficiency, phagocytosis and
cytotoxicity of monocytes increase and oxidative burst is enhanced
[21,42]. Additionally, increased maturation into macrophages was
observed after zinc depletion, suggesting that low zinc status pro-
motes differentiation of monocytes [42] (Fig. 1). Conversely, acti-
vation of these cells by the adaptive immune system is impaired
during zinc deficiency. This is due to decreased T helper type 1
(TH1)-cell-mediated secretion of interferon (IFN)-g [43], a TH1
cytokine of paramount importance for activation of APCs [44].
Moreover, zinc deficiency reduces the generation of IL-12 by
monocytes and macrophages [36,45]. IL-12 is an important regu-
lator of TH1-cell differentiation [46], making both IL-12 and IFN-g
critical cytokines for phagocytic activation by T-cells [36]. Thus,
host defense via phagocytosis and oxidative burst is maintained
during zinc deficiency, but ROS generation in monocytes and
macrophages seems to be less dependent on adaptive immunity
and cellular communication.
Several reports focus on zinc-induced release of pro-
inflammatory cytokines in vitro (IL-1, IL-6 and tumor necrosis fac-
tor (TNF)-a) [4,21,47]. In monocytes, zinc influences the secretion of
pro-inflammatory cytokines in a concentration-depended manner
60 M. Maares, H. Haase / Archives of Biochemistry and Biophysics 611 (2016) 58e65

Fig. 1. Innate and adaptive immunity during zinc deficiency. Overview of innate and adaptive immune cells and their interactions during zinc deficiency. For reasons of clarity only
selected cells and their mediated operations are shown. Immune cell numbers are, in most cases, decreased during zinc deficiency. Immediate immune defense against pathogens is
still maintained, because phagocytosis and oxidative burst are not declined in macrophages and monocytes, unless zinc deficiency becomes too severe. Cytokine release is
particularly impaired leading to altered intercellular communication and regulation.

e both enhancing and inhibiting cytokine release [4]. Low zinc
concentrations increase LPS-induced secretion of pro-
inflammatory cytokines, whereas higher concentrations nega-
tively affect cytokine production in monocytes in vitro. However,
the specific amount of zinc, which influences cytokine release,
depends on the cell model and experimental conditions. In human
peripheral blood mononuclear cells (PBMC), incubation with zinc
concentrations of 100 mM in LPS-free medium led to stimulation of
mRNA expression and release of IL-6, IL-1b, and TNF-a, suggesting
that high zinc concentrations stimulate monokine release in vitro
[48e50]. Moreover, when incubated simultaneously under “non-
stimulatory concentrations” (<100 mM zinc) zinc potentiated the
LPS effect, leading to increased secretion of cytokines [17,51]. In the
human cell line Mono Mac 1, 25 mM zinc was sufficient to down-
regulate mRNA levels of TNF-a and IL-1b after incubation with LPS,
whereas 1 mM zinc induced cytokine release [4,52]. However, in this
study zinc-incubation was conducted in the presence of pyrithione,
an ionophore that facilitates zinc absorption [52]. Findings of
cytokine release in zinc-deficient states are inconsistent and vary
depending on cell line, experimental condition and duration of zinc
depletion. In HL-60 cells, a promyelocytic cell line, zinc deficiency
augmented PMA-stimulated release of IL-1b, TNF-a, and IL-8
[33,47]. This was due to downregulation of A20, a protein which
inhibits cytokine production on the molecular level [47,53].
Furthermore, in vivo studies with mice showed that zinc depriva-
tion by TPEN increases levels of IL-1b and IL-6 after LPS-injection
[54]. In contrast, cytokine production is decreased by mild zinc
deficiency in human PBMC [21], whereas phagocytosis and oxida-
tive burst are not affected, reinforcing the assumption of a shift
away from intercellular communication via cytokines, concen-
trating the cellular activity on direct anti-pathogenic functions [21].
It has been postulated that a reprogramming of the immune system
occurs during zinc deficiency [55]. Such a shift from adaptive to
predominantly innate immunity and immediate host defense
would be accompanied by a decreased requirement for communi-
cation between innate and adaptive immune cells by cytokines.
Instead, monocytes and macrophages focus on phagocytosis and
oxidative burst during zinc deficiency.
On the molecular level, zinc regulates secretion of pro-
inflammatory cytokines by monocytes through modulating tran-
scription of their genes via activation or inhibition of the nuclear
factor-kB (NF-kB) [4,24]. The underlying molecular pathway is
based on Toll-like receptor (TLR)-4 signaling and its modulation by
zinc signals [7] (Fig. 2). TLR-4 is activated by conserved molecular
structures associated with pathogens, such as LPS [7,56], initiating
two different signaling pathways, either depending on the myeloid
differentiation primary response gene 88 (MyD88) or on Toll/IL-1R
domain-containing adapter inducing interferon-b (TRIF). The
MyD88-pathway leads to production of cytokines via NF-kB and
was shown to be activated by fast zinc signals, which occur in a few
seconds or minutes after triggering of the receptor [6]. In contrast,
TRIF-dependent signals are inhibited by zinc, resulting in decreased
IFN-b-production by reduced activation of IFN regulatory factor 3
(IRF3) [56]. Furthermore, zinc also affects TLR-4-mediated cytokine
release via cyclic nucleotide signals. Cyclic nucleotide phosphodi-
esterases (PDEs) degrade the second messengers cyclic adenosine
monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP) and depend on low zinc concentrations for their activity.
Conversely, higher zinc concentrations inhibit PDE activity, result-
ing in elevated cGMP, which cross-activates protein kinase A (PKA).
Through inhibitory phosphorylation of Raf1, this finally leads to
impairment of NF-kB activation. Yet another type of NF-kB-regu-
lation by zinc was found in HL-60 cells, in which the zinc finger
protein A20 is upregulated by zinc. Increased A20 then suppresses
 M. Maares, H. Haase / Archives of Biochemistry and Biophysics 611 (2016) 58e65 61

Fig. 2. Role of TLR-4 and zinc in antigen presenting cells. The LPS-induced MyD88-pathway leads to pro-inflammatory cytokine release and, together with increased levels of TRIF-
dependent IFN-b, NF-kB-activation triggers expression of the inducible nitric oxide synthase (iNOS). Upregulation of zinc exporters (ZnT) and downregulation of the zinc importer
ZIP6 via TRIF-dependent signaling result in decreased intracellular free zinc, subsequently leading to increased transport of major histocompatibility complex (MHC) class II
molecules to the plasma membrane and cell maturation. Broken lines implicate a series of different steps that are not depicted in detail for reasons of clarity.

TLR-induced activation of NF-kB leading to downregulated cyto-
kines [34,57]. In fact, in comparison to zinc sufficient HL-60 cells,
zinc deficiency led to decreased A20 mRNA levels, relieving its
inhibitory effect on NF-kB, followed by augmented cytokine release
[53]. Hence, zinc signals are required for NF-kB activation and
subsequent cytokine production. In the presence of critically
decreased or elevated intracellular zinc concentrations, these NF-
kB-activating pathways are inhibited, resulting in impaired cyto-
kine release.
2.3. Natural killer cells
Natural killer (NK-) cells are lymphocytes that are essential for
maintaining the innate immune response and host defense against
viral infections and tumors. They recognize and kill infected and
transformed cells through cytotoxic mechanisms. The expression of
major histocompatibility complex (MHC) class I molecules on the
cell surface is often downregulated in tumors and virally infected
cells, hiding them from cytotoxic T-cells, which recognize their
target cells by antigens presented on MHC I. In contrast, NK-cells
can detect these cells via missing antigen presentation [22,58].
Similar to the other innate immune cells, NK-cell activity and
function is zinc-dependent. Impaired NK-cell function was reported
in zinc-deficient humans [38,59] and after in vitro treatment with a
zinc chelator [38]. This was mainly due to decreased stimulation by
decreased T-cell-secreted IL-2 [60]. So far, only effects of extracel-
lular added zinc have been reported - not specifying its intracellular
role in NK-cell activity.
Zinc supplementation significantly increased NK-cell numbers
in whole blood cultures [61] and NK-cell activity in vivo [62],
whereas zinc depletion with TPEN did not lead to a decrease in the
number of NK-cells [61]. NK-cells, as all other leukocytes, are
generated from pluripotent hematopoietic stem cells in the bone
marrow that express the cluster of differentiation protein (CD) 34þ
on their surface [63]. Differentiation of a CD34þ common he-
matopoietic progenitor cell toward NK-cells has been observed to
be augmented by moderate extracellular zinc concentrations [64],
implying an involvement of zinc in NK-cell formation and
differentiation.
On the functional level, killer inhibitory receptors (KIR) on the
plasma membrane of NK-cells, which detect the expression of MHC
I molecules on the surface of the target cell and inhibit cytotoxic
mechanisms, are modulated by zinc. Zinc is required for multi-
merization of KIR [65] and its interaction with MHC I molecules,
while stimulation of the killing process is not zinc-dependent [66].
Thus, during zinc deficiency these inhibitory signals and the proper
interaction with MHC I on target cells could be impaired and lead to
unspecific killing. However, the latter might be only of limited
relevance in light of the abovementioned functional impairment of
NK-cell cytotoxic activities during zinc deficiency.
Besides their cytotoxic defense mechanisms, NK-cells also
regulate the immune response and facilitate the activation of im-
mune cells by secreting cytokines, which was shown to be
enhanced after zinc supplementation [61]. One of these cytokines is
IFN-g, which activates dendritic cells, promotes their maturation
and initiates immune response by T helper cells (TH)-cells and their
differentiation, which is discussed in detail below [61].
2.4. Dendritic cells
Other important leukocytes in innate immune defense are
dendritic cells (DC), which are often described as a linker between
innate and adaptive immune system. They are essential for the
innate immune system, secreting cytokines (IL-2, IL-6, IL-10; IL-12,
TNF-a [67e69]), and activating NK- and NKT-cells [58,70]. Addi-
tionally, they provide information about dimension and nature of
infection and communicate with T-cells via antigen presentation
[71]. Intracellular zinc concentrations play a critical role in DC
function and activity. LPS stimulation of murine dendritic cells led
to downregulation of the zinc importer Zrt/Irt-like protein 6 (ZIP6)
and upregulation of zinc exporters via TLR-4, resulting in decreased
free zinc and increased cell maturation [72]. In fact, reduction of
intracellular zinc was found to be crucial for surface expression of
MHC II molecules [72], which present antigens to CD4þT-cells,
hereby activating them during an infection. In immature DC, MHC II
is located in lysosomes and endosomes [73]. Transport of MHC II
molecules from these compartments to the plasma membrane is
inhibited by zinc and a reduction of cellular zinc is required to
enable antigen presentation and hereby communication with
adaptive immunity [72] (Fig. 2).
62 M. Maares, H. Haase / Archives of Biochemistry and Biophysics 611 (2016) 58e65
3. Adaptive immune system
The adaptive immune system is based on T- and B-lymphocytes,
which express specific receptors on their surface to detect antigens
- T-cell receptor (TCR) and B-cell receptor (BCR) [74,75]. Antigens
are defined as structures, which are recognized by these receptors
or antibodies (¼ soluble BCR) and are mainly proteins and peptides,
next to carbohydrates, lipids or any synthetic structure. Their spe-
cific recognition by these receptors results in a selective expansion
in numbers and activation of the T- and B-cell clones carrying a
matching receptor, leading to the participation of these highly
antigen-specific cells in the immune response. Some of these cells
persist as memory cells even after the end of an infection. Hence,
subsequent contacts with the same antigen lead to a faster and
more efficient response of the adaptive immune system.
Altered zinc homeostasis influences lymphocyte activity, func-
tion, and development by directly affecting their formation (lym-
phopoiesis) and cytokine secretion (Fig. 1) or indirectly due to
impaired stimulation by innate immune cells [2,76].
3.1. T-cells
T-cells express CD4þ or CD8þ co-receptors on their surface,
defining their function. These co-receptors lead to enhanced
interaction with MHC molecules on the surface of target cells
(CD4þ/MHC II; CD8þ/MHC I) and regulate the specific presentation
of antigens to the TCR. Depending on their co-receptor, T-cells are
divided in cytotoxic CD8þ T-cells and CD4þ T helper (TH)-cells
[77,78]. TH-cells promote functions of other immune cells, whereas
cytotoxic T-cells recognize and eliminate virally infected and tumor
cells [6].
The thymus is a lymphoid organ, where maturation of T-cells
takes place. Several reports describe the occurrence of thymic at-
rophy due to zinc deficiency in human children [79,80] and animals
in vivo [81], reporting a serious size reduction of the thymus, which
is caused by increased glucocorticoid levels and enhanced
apoptosis of pre T-cells. Subsequently, the amount of mature T-cells
significantly declines, leading to reduced activity of CD8þ cytotoxic
T-cells and CD4þ TH-cells [76,82,83].
This crucial decrease in T-cells during zinc deficiency is not only
caused by enhanced apoptosis of pre T-cells, but also by impaired
thymulin activity [1,84]. Thymulin is a thymic peptide hormone
that requires zinc for its activity and is crucial for T-cell differenti-
ation and function [84,85]. Additionally, it induces IL-2 cytokine
secretion and CD8þ cell proliferation [86,87]. In humans with mild
zinc deficiency, thymulin activity and number of T-cells decrease
significantly [1]. Similarly, thymulin activity was diminished in
zinc-deficient mice without thymic atrophy and could be restored
by zinc supplementation [84].
Decreased proliferation and differentiation affect TH-cell func-
tion and cytokine production. There are several types of TH-cells
and their balance is of crucial importance for an effective immune
response. TH1- and TH2-cells antagonize each other, directing the
immune response either toward cellular immunity (TH1), especially
activation of macrophages, or toward humoral immunity (TH2),
mediated by B-cell antibody production [88]. TH1 cytokines (IL-2,
IFN-g, and TNF-a) are reduced by zinc deficiency [43,89,90]. The
TH1 cytokine IFN-g mainly stimulates TH1 development, macro-
phages, and DCs and induces MHC molecule expression [44,45].
Besides, IFN-g attenuates TH2 [91]. IL-2 is an important cytokine for
T-cell proliferation, activation, and differentiation and additionally
represses TH2 [89,92]. Because IL-2 stimulates NK-cells and mono-
cytes, impaired IL-2 secretion alters their activity and function as
well [47,93]. Production of TH1 cytokines is decreased in zinc-
deficient states, whereas TH2 cytokines (IL-4, IL-6, IL-10) are not
affected, leading to a net shift of the TH1/TH2 ratio toward TH2
[43,90]. Thus, zinc influences the TH1/TH2 balance, resulting in
altered immune function due to decreased TH1 cytokine secretion
[77].
Several studies investigated the correlation of TH1 cytokine
release and zinc concentration. Studies with the T-cell line Hut-78
analyzed cytokine release after incubation with extremely low
(1 mM), moderate (15 mM) and high zinc concentrations
(50e100 mM) [5,94]. While cells with zinc deficiency (incubated
with 1 mM zinc) showed significant decrease in IL-2, TNF-a, IFN-g,
and the IL-2 receptor alpha chain (IL-2Ra) gene expression [5], high
zinc supplementation led to mild mRNA-downregulation and
decreased production of these cytokines compared to incubation
with 15 mM zinc [94]. Zinc affects mRNA levels of cytokines via NF-
kB inhibition or induction, and, accordingly, NF-kB DNA-binding
activity in Hut-78 cells was also decreased in the same
concentration-dependent manner [94]. Furthermore, TNF-a is
known to stimulate NF-kB [24], thus downregulation of TNF-a
might also affect NF-kB activity [94]. In addition to the molecular
mechanism of cytokine expression via the protein kinase C (PKC)/
Raf1/NF-kB pathway [4,52], it has been reported that intracellular
zinc levels modulate TH1 cell differentiation via IFN-g and T-box
transcription factor (T-bet) upregulation in Hut-78 cells after
Concanavalin A (Con A)-induced TCR-stimulation [45]. More spe-
cifically, increase of intracellular free zinc after Con A stimulation in
cells treated with 5 mM zinc is suggested to enhance IFN-g, T-bet,
and IL-12 receptor beta 2 subunit (IL-12Rb2) via activated PKC-q.
Because IFN-g, T-bet, and IL-12Rb2 are important for differentiation
of naïve CD4þT-cells toward TH1 [44], upregulation of these cyto-
kines emphasizes that zinc promotes TH1 differentiation [45].
Regulatory T-cells (Tregs) play a special role in controlling
adaptive and innate immunity by suppressing immune cells
[16,95]. Several studies report unwanted T-cell-mediated immune
responses and their prevention by zinc treatment in vivo and
in vitro [16,96e98]. Moderate zinc supplementation was suggested
as means to control allergen specific immune reactions by regula-
tion of the TH1/TH2 ratio and Treg activity [43,95]. Zinc was observed
to modulate the allergic immune response by increasing the
number of regulatory T-cells, limited allergen-induced immune cell
proliferation, and development of the immune response toward
TH1 by decreased TH2 cytokine IL-10 and enhanced IFN-g in human
PBMC after incubation with timothy grass allergen and 50 mM zinc
[16]. Conversely, in a mixed lymphocyte culture the addition of
50 mM zinc induced Tregs but decreased IFN-g, suggesting a pre-
vention of allograft rejection e rejection of transplanted tissue from
the same species [99]. These immunomodulatory effects of zinc by
regulation of cytokine signaling in T-cells were also reported in vivo
[98]. Here, allogeneic reactions were suppressed after supple-
mentation with high zinc doses in vitro and in vivo (80 mg/day;
1wk) [96,100].
TH17 are another subpopulation of TH-cells, which induces the
recruitment of neutrophil granulocytes and regulates cell-mediated
immune response against extracellular pathogens [101]. Cytokines
released by TH17-cells promote inflammation and are connected
with autoimmune diseases [102]. Beneficial effects of zinc supple-
mentation were observed in investigations on zinc and TH17-
mediated autoimmune diseases. In mice with experimental auto-
immune encephalomyelitis (EAE), an experimental model for
multiple sclerosis, moderate zinc doses led to declined TH17 cell
numbers and diminished EAE severity [97,103]. This was accom-
panied by an augmented number of inducible Tregs in the central
nervous system [103].
Treatment of individuals with pharmacological zinc supple-
mentation has a profound effect on the immune system. Similarly
to the other immune cells, supplementation of zinc-deficient
 M. Maares, H. Haase / Archives of Biochemistry and Biophysics 611 (2016) 58e65
individuals can reverse the negative effects of zinc deficiency on T-
cells [41,104]. Treatment of individuals with normal zinc levels was
shown to modulate the immune system dependent on the sup-
plemented amount of zinc. Moderate zinc concentrations improve
immune function and extenuate unwanted T-cell-mediated im-
mune response [97,103], whereas high zinc doses inhibit immune
function [17,100].
3.2. B-cells
B-cells play an essential role in the humoral immune response
by producing antibodies [74]. Because lymphopoiesis is impaired
during zinc deficiency, pre-B-cell numbers decrease during zinc
deprivation [83] (Fig. 1). Interestingly, an animal study with zinc-
deficient mice showed a strong decrease in lymphopoiesis for T-
cells, whereas B-cells and their maturation in the bone marrow
were less affected [2]. Comparable to T-cells, the decreased pre B-
cell number in zinc-deficient states is connected to glucocorticoid
metabolism and increased apoptosis [105]. A recent report by
Hojyo et al. has provided new insights into the role of zinc in B-cell
development. The antigen receptor BCR, expressed on the surface
of immature and mature B-cells, controls the activation status of B-
cells and regulates their proliferation [106]. The zinc transporter
ZIP10 regulates B-cell function and has an important role in hu-
moral immunity by modulating BCR signals [106] and preventing
apoptosis in B-cells [8].
In zinc-deficient states, a reduced immune response to vacci-
nation in vivo was reported several times [107e109], suggesting a
possible enhancement of antibody formation by zinc supplemen-
tation [110]. Multiple studies investigated the impact of zinc sup-
plementation on vaccination leading to different results, mainly
due to heterogeneity of experimental design (as reviewed in
Ref. [19]). In general, simultaneous supplementation of high
amounts of zinc at the time of vaccination resulted in poorer out-
comes, whereas zinc treatment in advance of vaccination seems to
be a far more promising way to improve the antibody response
[109e112].
4. Conclusion
The role of zinc in the immune system has been investigated in
depth. As discussed above, altered zinc homeostasis critically in-
fluences innate and adaptive immunity, and therefore host defense
and the immune response in general.
Zinc supplementation can reverse the negative effects of zinc
deficiency, including impaired immune cell development,
compromised T-cell-mediated immune response, decreased
oxidative burst and many more. The potential benefits of zinc
supplementation go from anti-inflammatory and immunomodu-
latory effects, to prevention of allergies and autoimmunity, or even
suppression of allogenic reactions. A more detailed understanding
of the molecular effects of zinc and their controlled manipulation
might prove to be a useful future tool for targeted modulation of the
immune system with very limited side effects.
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