Immune-Based Modulation of Adult Hippocampal Neurogenesis, Link to Systemic Th1/Th2 Balance

Abstract

The interaction between adaptive immune system and the central nervous system
(CNS) has been extensively studied for decades. A series of researches have indicated
that systemic T cells, particularly CD4+ T cells are involved in supporting
fundamental processes of brain functional integrity, such as in the maintenance of
brain plasticity including spatial learning and memory, and neurogenesis. Moreover,
recent data from our laboratory indicate alteration of systemic T helper cell type 1
(Th1)/Th2 balance is tightly linked to hippocampal neurogenesis and working
memory. In this review, we summarize current knowledge of the systemic Th1/Th2
balance, describe how this skewing appears to operate in hippocampal neurogenesis,
and reinforce the theory of interaction mechanism of these two vital systems

Full text

Immune-Based Modulation of Adult Hippocampal Neurogenesis, Link to
Systemic Th1/Th2 Balance
Fangfang Qi, Yucen Xia, Zejie Zuo, Yingying Wu, Junhua Yang, Xiao Wang and Zhibin Yao*
Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, PR China
*Corresponding author: Zhibin Yao, Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road,
Guangzhou 510080, PR China, Tel: + 86 20 87332638; Fax: + 86 20 87330709; E-mail: yao.zb@163.com
Received date: 23 December 2014; Accepted date: 11 February 2015; Published date: 16 February 2015
Copyright: © 2015 Qi F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The interaction between adaptive immune system and the Central Nervous System (CNS) has been extensively
studied for decades. A series of researches have indicated that systemic T cells, particularly CD4+ T cells are
involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of brain
plasticity including spatial learning and memory, and neurogenesis. Moreover, recent data from our laboratory
indicate alteration of systemic T helper cell type 1 (Th1)/Th2 balance is tightly linked to hippocampal neurogenesis
and working memory. In this review, we summarize current knowledge of the systemic Th1/Th2 balance, describe
how this skewing appears to operate in hippocampal neurogenesis, and reinforce the theory of interaction
mechanism of these two vital systems.
Keywords: Th bias; Dentate gyrus; Immune system; Correlation;
Cytokine; Neurogenesis
Introduction
Brain has not been considered as a classic immunologically
privileged organ recent years [1,2], in which, peripheral immune cells
could not through the blood brain barrier into the CNS under normal
physiological state [3]. Current researches in neuroimmune
interactions focus on immune cytokines- or cells-based regulation of
cognitive function and neural plasticity rather than traditional brain
damage [4]. Hippocampal neurogenesis continues in the Dentate
Gyrus (DG) of the hippocampus throughout adult life. Adaptive
peripheral immune activation regulates proliferation of neural
precursor cells in adult hippocampus [5-7]. Recent researches also
provide excellent evidence that stress-induced hippocampal
neurogenesis alteration in DG is accompanied by Th1/Th2 balance
changing in the periphery [8,9]. Together with our recent studies
[10,11], we have proposed a concept that underlying mechanism of
immune system affecting the CNS is not just regulated by a certain
cytokine but rather regulated by many cytokines [12], which are
correlated with systemic Th1/Th2 cytokine balance, for modulation of
elaborated brain functions. Importantly, other reports indeed shed
light on the correlation between systemic Th1/Th2 balance and adult
hippocampal neurogenesis [8,13]; although recent data indicate that
the dichotomous categorization of helper T lymphocyte into Th1 and
Th2 has become gradually blurred. We purpose the hypothesis that the
alterations in adult hippocampal neurogenesis could be related to a
differential regulation of systemic Th1/Th2 cytokine balance. In this
article, we focused on some of the most recent results on systemic
Th1/Th2 bias within a normal range on adult hippocampal
neurogenesis and review results obtained in our laboratory. We
summarize first, the effects of systemic Th1 bias on adult
hippocampus; second the effects of Th2 bias on adult hippocampus;
thirdly, how and where Th1/Th2 balance influences adult
hippocampal neurogenesis. We end with a supposition of the effects of
excessive helper T cell bias on hippocampal neurogenesis under
pathological conditions.
Th1 bias and adult hippocampal neurogenesis
Under normal or physiological condition, it has been demonstrated
that systemic Th1 bias is correlated with adult hippocampal
neurogenesis. A model of modest exercise-training, which is widely
recognized to increase adult hippocampal neurogenesis, causes Th1
bias via up-regulating interferon gamma (IFN-γ) levels in the
periphery [11]. We recently showed that influenza A (H1N1)
vaccination during early pregnancy transiently promote adult
hippocampal neurogenesis, potentially via the restoration of the
balance of Th1/Th2 [10]. Pregnant mice display a decrease in
hippocampal neurogenesis followed by a down-regulation in systemic
Th1/Th2 balance [14,15]. However, this neuronal deficit can be
reversed by influenza vaccination, which is known to induce Th1 bias
during early pregnancy [10]. Importantly, there exists a positive
correlation between the interferon (IFN)-γ to interleukin (IL)-4 ratio
and hippocampal Brain-derived neurotrophic factor (BDNF) levels,
further supporting our viewpoint [10]. Furthermore, one mouse
model of rheumatoid arthritis used by Wolf, S.A. et al. characterized
by a Th1-dependent local inflammation of the knee joints increases
proliferation of neural precursor cells in the adult hippocampus [5], as
can be seen in Table 1. Interestingly, the intensity of observed change
in Th1 bias might be antigen-specific. This is exemplified in a study
Teixeira L et al. who observed a strong Th1-type immune response
induced by the protozoan parasite [16], which can impair adult
neurogenesis reflected by a decline in the neural stem cell pool at peak
parasitemia [17-23]. This question was, thus, not within the scope of
the present article for its pathological condition. Together, these
findings confirm that peripheral immune response such as Th1 bias
indeed correlates with adult hippocampal progenitor cells niche,
whereby adjusting to cognitive function. However, the range of Th1
bias remains to be explored in further research [24-35].
Vaccines & Vaccination Qi et al., J Vaccines Vaccin 2015, 6:2
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Th1/Th2 balance Objective Results References
Th1 bias Study mechanism of stress with cognitive deficit Th1-type cytokine correlates to a better
performance
Palumboa et al. [9]
Th1 bias Study association of Glatiramer of adult
neurogenesis
Glatiramer induce Th1bias
following increasing neurogenesis
Palumboa et al., He et al. [9,13]
Th1 bias Study association of exercise of neurogenesis Moderate exercise produces Th1-like cytokine Baum et al. [11]
Th1 bias Study association of A(H1N1) Vaccination of
neurogenesis
A(H1N1) Vaccination causes Th1-like immune
response
Xia et al. [10]
Th1 bias Adaptive immune response increases
hippocampal proliferation
A rheumatoid arthritis model,
Th1-dependent local inflammation
Wolf et al. [5]
Th2 bias Study the effect of zinc on Th1/Th2 ratio in
elderly individuals
Decrease of Th1/Th2 ratio with aging Kahmann et al. [24]
Th2 bias Altered cytokine production in the elderly Decrease of Th1/Th2 ratio with aging Rink et al. [22]
Th2 bias Shift toward destructive Th2 inflammation in
brain
T helper type 2 (Th2) in choroid plexus
inflammation with aging
Baruch et al. [36]
Th2 bias Th2 bias at the maternal/fetal interface in
pregnancy
Decrease of neurogenesis in pregnancy related
in Th2 bias
Piao et al. [15]
Rolls et al. [14]
Table 1: Association of adult hippocampal neurogenesis or cognitive function with Th1/Th2 balance.
Th2 bias and adult hippocampal neurogenesis
The previously discussed findings clearly show that reestablishing
the systemic Th1/Th2 cytokine balance could restore adult
hippocampal and neurocognition [8,13]. As we expected, Peripheral
Blood Mononuclear Cell (PBMC) activated ex vivo with external
antigen exhibited an age-related decline in Th1 cell response, shown
by the decline in the frequency of IFN-γ-secreting memory T cells
using Enzyme-Linked Immunospot Assay (ELISPOT) or flow
cytometry. The reduced frequency of IFN-γ-secreting T cells is
accompanied by an increased Th2 response in elderly subjects [18]. So
the cognitive impairment observed in aged subjected might be
partially explained by increasing destructive Th2 inflammation in the
Choroid Plexus (CP) accompany by inducing expression of CCL11
[19], a chemokine elevated in the Cerebrospinal Fluid (CSF) and
plasma in the aged human and mice [20]. It is important to note that
the Th2 inflammation was observed in normal aging. So it is within
the scope of physiological conditions. In line with this, accumulating
evidence supports the relationship of decrease in Th1/Th2 cytokine
balance and aging-related cognitive decline [21,22]. Interestingly, the
prominent Th2 bias can be reversed by zinc supplementation in aging
individuals [23,24], as can be seen in Table 1. However, whether aging-
related cognitive impairment can be restored after zinc
supplementation remains elusive. It requires further studies to
elaborate this question.
Besides aging-related Th2 bias, studies indicated that decreased
hippocampal neurogenesis may link to Th2 bias at the maternal/fetal
interface during pregnancy [14,15]. Although IL-4-producing T cells
were recently identified as anti-inflammatory cytokine and shown to
support neural regeneration under pathological conditions [25,26],
high levels of IL-4 induced the choroid plexus to produce CCL11 [19],
which is associated with cognitive decline. Notably, the typical
cytokine IL-4 is not completely equivalent to the Th2-derived
cytokines. Notwithstanding, these data indeed increase the probability
that Th2-derived cytokines correlate with decreased hippocampal
neurogenesis and cognitive impairment.
How systemic Th1/Th2 cytokine balance modulates adult
hippocampal neurogenesis
Systemic Th1/Th2 cytokine balance is known for their role in many
immune responses [27,28]. It has recently been implicated in the
regulation of adult hippocampal neurogenesis [29-31]. However, the
mechanism by which Th1/Th2 influences neuronal proliferation
remains unknown. Here we present that the possible cytokines
modulate adult hippocampal neurogenesis involved in Th1/Th2
cytokine balance. Therefore, we focus on the role of IFN-γ and IL-4,
which serve as the classical representative of Th1 cytokines and Th2
cytokines, respectively. For one thing, recent data reveals that the pro-
inflammatory cytokine, IFN-γ but not TNF-a, enhances neuronal
differentiation, rapidly increasing βIII-tubulin positive cell numbers in
certain vitro culture [32]. Moreover, R. Baron et al. have also
demonstrated that IFN-γ enhances neurogenesis in the DG and
improves the spatial learning abilities both in adult and aged animal
models. IFN-γ Tg mice performing better spatial cognitive function
than naïve mice further confirms the role of IFN-γ implicated in the
fate of neural precursor cells (NPCs) in the hippocampus [33]. It is
important to note that the level of IFN-γ is relative low or limited
amounts at above experiments. In contrast, high levels of IFN-γ
inhibits adult hippocampal neurogenesis via the activation of other
pro-inflammatory cytokines such as TNF-a, IL-1β, IL-6. These results
imply that low-level inflammatory cytokines aid neurogenesis but
high- level ones impair neurogenesis, reminiscent of cytological
changes following homeostatic neurogenic niche [12]. For another
thing, the role of IL-4 on neurogenesis and cognitive function is well
documented, but the explanations for it are very controversial.
Consistent with our results, Nunan R et al. have well demonstrated
that VIP, a neuropeptide released by the interneurons in DG, enhances
Citation: Qi F, Xia Y, Zuo Z, Wu Y, Yang J, et al. (2015) Immune-Based Modulation of Adult Hippocampal Neurogenesis, Link to Systemic
Th1/Th2 Balance. J Vaccines Vaccin 6: 274. doi:10.4172/2157-7560.1000274
Page 2 of 4
J Vaccines Vaccin
ISSN:2157-7560 JVV, an open access journal Volume 6 • Issue 2 • 1000274

the pro-neurogenic effect of microglia via IL-4 release [34]. However, a
dominant shift in favor of Th2 bias identified by the IFN-γ: IL-4 ratio
indeed regulates negatively hippocampal neurogenesis independent of
IL-4 level [8,10]. The underlying mechanism by which the Th2 bias
regulates hippocampal neurogenesis is incompletely understood. A
recent study from our laboratory reveals that increased Th1/Th2
balance transiently promotes neurocognition, probably via the
alterations of cytokines expression in peripheral and neurochemicals
expression in the hippocampus (unpublished data).
Figure 1: A simplified diagram describing relations between
hippocampal microglia phenotype, systemic Th1/Th2 bias and
neurobehavioral functions under in terms of physiological
conditions and pathological conditions. (a) Blue/red colors
represent increased/decline in hippocampal neurogenesis,
respectively. (b) Systemic Th1/Th2 cytokine balance correlates with
hippocampal neurogenesis [8-10], followed by M2 (alternatively
activated) or M1 (classically activated) polarization of microglia in
the present study. (c) There is less likely exist a linear relationship
between them on basis of continuous invasion of Th1 cells in
autoimmune diseases involved with cognitive decline, although
systemic Th1 bias is positively associated with increased in neural
proliferation [35]. (d) Proper Th2 bias or strong Th2 inflammation
is associated with cognitive decline [36].
Conclusion
This review collectively illustrates the role for systemic Th1/Th2
balance in the regulation of adult hippocampal neurogenesis. It is
attempting assume that changes of immune status in periphery
regulate brain functions. Although Th1-type cytokines (IFN-γ, TNF-a
et al.) are regard as pro-inflammatory factors implicated in the
detrimental effects of neural proliferation and Th2-type cytokines
(IL-4, IL-10 et al.) are anti-inflammatory factors, it is likely that proper
cytokine balance is sufficient to modulate hippocampal neurogenesis
for normal homeostasis in brain. In our recent studies, influenza
vaccination including A (H1N1) vaccine and Seasonal vaccine elicit
Th1 like serum cytokine response accompanied by a remarkable
neurobeneficial profile of cytokines and neurotrophic factors in the
hippocampus [10,12]. Notably, systemic Th1/Th2 bias in this review is
not pathological, but in normal range. Thus, altered adult
hippocampal neurogenesis is transient both in pregnancy and exercise
models. However, the fortissimo or excessive Th1/Th2 unbalance in
autoimmune disease and neurodegenerative disease was, thus, not
within the scope of the present investigation. Even so, the excessive
Th1/Th2 unbalance may still correlate to adult hippocampal
neurogenesis (Figure 1).
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Citation: Qi F, Xia Y, Zuo Z, Wu Y, Yang J, et al. (2015) Immune-Based Modulation of Adult Hippocampal Neurogenesis, Link to Systemic
Th1/Th2 Balance. J Vaccines Vaccin 6: 274. doi:10.4172/2157-7560.1000274
Page 4 of 4
J Vaccines Vaccin
ISSN:2157-7560 JVV, an open access journal Volume 6 • Issue 2 • 1000274