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IL-4 in the Brain: A Cytokine To Remember

Jonathan KipnisSachin P. Gadani, James C. Cronk, Geoffrey T. Norris and

http://www.jimmunol.org/content/189/9/4213doi: 10.4049/jimmunol.1202246

2012; 189:4213-4219; ;J Immunol 

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IL-4 in the Brain: A Cytokine To RememberSachin P. Gadani,*,†,1 James C. Cronk,*,†,1 Geoffrey T. Norris,*,1 and Jonathan Kipnis*,†

IL-4 has been extensively studied in the context of itsrole in immunity. Accumulating evidence indicates,however, that it also plays a critical role in higher func-tions of the normal brain, such as memory and learning.In this review, we summarize current knowledge of thebasic immunology of IL-4, describe how and where thiscytokine appears to operate in normal brain function,and propose a hypothesis concerning its potential rolein neurological pathologies. The Journal of Immunol-ogy, 2012, 189: 4213–4219.

The brain is frequently studied in isolation from theimmune system. The principal reason for this is clear:conventional wisdom has long held that the brain is

shielded from immune-cell infiltration by the blood–brainbarrier (BBB). When this protective interface is breached andthe immune system freely interacts with the brain, it fre-quently results in autoimmune attacks and other debilitatingimmune-related conditions. In reality, however, neuroim-mune interactions appear to be crucial for everyday brainfunction. Mice in which adaptive immunity is absent oracutely suppressed exhibit cognitive impairment, which is ex-pressed in their inability to perform spatial learning tasks, adefect that is reversible upon restoration of the T cell pool (1–3). One likely location for neuroimmune interactions is thesubarachnoid space, a cerebrospinal fluid-filled compartmentof the meninges. Healthy human cerebrospinal fluid contains∼150,000 leukocytes (∼10,000 in the C57B6 mouse [ourlaboratory’s unpublished observations]), most of which arecentral memory T cells (4). A recent study from our labora-tory showed that performance of a learning and memory taskis followed by an increase in the numbers and activation ofT cells in the meninges. Moreover, administration of anti-VLA4, which prevents normal extravasation of T cells (andmonocytes) into the cerebrospinal fluid, produced a cognitiveimpairment similar to that seen in T cell-deficient mice (5).T cells in the cerebrospinal fluid appear ideally positioned to

communicate with the brain. In healthy individuals, however,T cells do not penetrate the brain parenchyma, and any suchcommunication must be mediated through a soluble mes-

senger. We recently showed that T cell-derived IL-4 is a criticalparticipant in higher brain functions such as memory andlearning (5). Mice that lack IL-4 demonstrate cognitive im-pairment in spatial learning tasks, and this can be reversed bytransplantation of IL-4–competent bone marrow (5). In thisarticle, we focus on the basic immunology of IL-4 as it per-tains to the CNS, and in particular to the question of how andwhere it operates to influence cognition. We end with a re-view of the literature on the role of IL-4 in several neuro-logical diseases.

IL-4 signaling

IL-4 is a cytokine that functions as a potent regulator ofimmunity secreted primarily by mast cells, Th2 cells, eosi-nophils, and basophils. Initially identified by Howard and Paul(6) as a comitogen of B cells, IL-4 was subsequently shownto be an important player in leukocyte survival under bothphysiological and pathological conditions (7, 8), such as Th2cell-mediated immunity (9, 10), IgE class switching in B cells(11), and tissue repair and homeostasis through “alternative”macrophage activation (12). Although granulocytes and type2 innate lymphoid cells (13) are capable of producing Th2cytokines, the majority of currently available literature, in-cluding our own studies, focus on Th2 T cells.The effect of IL-4 signaling is mediated through the IL-4R

a-chain (IL-4Ra). Upon binding to its ligand, IL-4Ra di-merizes either with the common g-chain to produce the type1 signaling complex, located mainly on hematopoietic cells,or with the IL-13Ra1 to produce the type 2 complex, whichis expressed also on nonhematopoietic cells (14, 15). The type1 signaling complex is critical for Th2 skewing of T cells andthe development of alternatively activated macrophages(AAMFs), whereas the type 2 complex plays a role in non-hematopoietic responses to IL-4 and IL-13, for example,airway hyperreactivity and mucous production (16). The roleof IL-13 in CNS function is understudied and merits furtherinvestigation.Upon activation, the type 1 complex signals through Janus

family kinases (JAK1 and JAK3), which phosphorylate andcreate docking sites for the transcription factor STAT6, whichthen dimerizes and translocates to the cell nucleus. Among its

*Department of Neuroscience and Graduate Program in Neuroscience, Center for Brain Im-munology andGlia,University of Virginia, Charlottesville, VA 22908; and †Medical ScientistTraining Program, School of Medicine, University of Virginia, Charlottesville, VA 22908

1S.P.G., J.C.C., and G.T.N. contributed equally to this review.

Received for publication August 13, 2012. Accepted for publication August 27, 2012.

This work was supported by National Institute on Aging, National Institutes of HealthGrant AG034113 (to J.K.).

Address correspondence and reprint requests to Dr. Jonathan Kipnis and Dr. Sachin P.Gadani, University of Virginia, 409 Lane Road, Charlottesville, VA 22908. E-mailaddresses: kipnis@virginia.edu (J.K.) and sg8th@virginia.edu (S.P.G.)

Abbreviations used in this article: AAMF, alternatively activated macrophage; AD,Alzheimer’s disease; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic fac-tor; EAE, experimental autoimmune encephalitis; GBM, glioblastoma multiforme; i.c.v.,intracerebroventricularly; IL-4Ra, IL-4R a-chain; LTP, long-term potentiation; MS,multiple sclerosis; MWM, Morris water maze.

Copyright� 2012 by TheAmerican Association of Immunologists, Inc. 0022-1767/12/$16.00

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other actions, STAT6 promotes transcription of GATA3 (aTh2 cell inducer) and MHCII (myeloid and B cells), andinduces IgE class switching in B cells (11, 17–19). JAK1 alsophosphorylates insulin receptor substrate-1 and -2, whichbecome activated and promote survival and growth throughthe PI3/AKT, PKB/mTOR, and other pathways (20).The type 2 receptors also signal through JAK family kinases

(JAK1 and TYK2), but are not expressed by T cells, and insteadare used by nonhematopoietic cells such as endothelial cellsand fibroblasts to respond to IL-4. As with type 1, much ofthe message of type 2 receptors is conveyed by STAT6, whichis phosphorylated and translocates to the nucleus upon ligandbinding. Type 2 receptors also serve as receptors for IL-13, acytokine with similarities to IL-4, and that first binds with theIL-13Ra1 and then dimerizes with IL-4Ra to produce thefamiliar signaling cascade (Fig. 1).

IL-4 as a mediator of T cell effects on brain function

Findings by our group and others have demonstrated a fun-damental role for T cells in cognition and brain homeostasis(2, 21–24). Mice that lack T lymphocytes exhibit cognitiveimpairment in learning tasks on the Morris water maze(MWM). An established behavior paradigm, the MWM takesplace over a week where mice are placed once daily in a largeplastic pool in which a platform is submerged in opaquewater. Salient visual cues are supplied in the testing room thatallow the mice to gradually learn the location of the platform.Over the course of several days, a healthy mouse will committhis location to memory and exhibit progressively faster escapelatency to the platform (25). Although T cell-deficient mice

spend considerably more time searching for the platform,MWM performance can be restored almost to the level ofwild-type mice by adoptive transfer of wild-type T cells or bybone marrow transplantation from wild-type to immune-deficient counterparts. In addition to their spatial learningdeficits, mice that lack both T and B cells (SCID, nude, orRag12/2 mice) exhibit reduction of adult neurogenesis (2, 24,26), an ongoing physiological process in which new neuronsare generated in specific zones of the adult brain (27). Wolfet al. (24) further identified CD4+ T cells as the key immunepopulation responsible for both adult neurogenesis and cog-nitive performance.Inflammatory cytokines such IL-1b and TNF have been

extensively studied in the brain, where they exert a negativeeffect on cognitive behavior, characterized by sickness, de-pression, and stress (28–30). We recently discovered that theeffect of IL-4 on cognition, in contrast, is beneficial. Aftermice undergo training in the MWM, their meningeal T cellsbecome activated and produce more IL-4 than untrainedcontrols (5). Absence of the ability to produce IL-4 in re-sponse to learning has conspicuous consequences, as observedin the severe learning defects exhibited by IL-42/2 mice (5).These defects can be reversed by transplantation with wild-type bone marrow or adoptive transfer of IL-4–competentT cells, whereas both T cells and transplanted bone marrowderived from IL-42/2 mice are ineffective. Furthermore, wild-type mice transplanted with IL-42/2 bone marrow subse-quently show learning impairment, reinforcing the role ofIL-4 in cognition and demonstrating its dynamic nature(5).The previously discussed findings clearly show that T cell-

derived IL-4 has a profound effect on cognition, but itsmechanism of action, given the stringent BBB, is unclear.Astrocytes, as described later, respond to IL-4 signaling andmight serve as a mediator between the immune effector cellsand the nervous responders. This possibility is supported bythe fact that in wild-type mice, but not in IL-4 knockout mice,training in the MWM is followed by astrocytic production ofbrain-derived neurotrophic factor (BDNF) (5). This protein,which is responsible for growth and survival of neurons andfor increased neuronal arborization of dendrites, has beenshown to have a positive effect on learning, and its absencein IL-4 knockout mice might explain their cognitive defects(31, 32).Another possible target for IL-4 is the meningeal myeloid

compartment, where lack of IL-4 creates a proinflammatorymeningeal immune response (5). Meningeal myeloid cells(CD11b+) in SCID mice produce more TNF than their wild-type counterparts (5). Adoptive transfer of wild-type T cells,but not of IL-4 knockout T cells, reduces this TNF produc-tion (5). Thus, IL-4 might be exerting its effect through ananti-inflammatory M2-skew (alternative activation) of men-ingeal macrophages, shown to be beneficial after CNS injury(33) and required for learning (34). Administration of M2-skewed macrophages, either intracerebroventricularly (i.c.v.)or i.v., improves MWM performance in immunocompro-mised animals (34). Whether these procognitive effects ofT cells through astrocytes and through M2 macrophages areseparate or linked processes remains to be investigated, but ineither case, they provide interesting avenues for productiveneuroimmune communication.

FIGURE 1. IL-4 signaling pathways. After IL-4 binding IL-4Ra, the IL-4R

is created by dimerization with the common g-chain (gc) to create the type 1

signaling complex or with IL-13Ra1 to create the type 2 complex. Both

receptors signal through STAT6, which is phosphorylated, dimerizes, and

traffics to the nucleus to function as a transcription factor for Th2, IgE, and

AAMF-associated genes. The type 1 receptor also activates IRS1 and/or IRS2,

leading to increased mitogenesis and inhibition of apoptosis through multiple

signaling pathways. The type 2 complex also responds to IL-13, and it can

signal other STAT molecules (i.e., STAT3) through the JAK family kinase

TYK2.

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Cellular targets of IL-4 in the brain

IL-4 plays important roles in a myriad of cellular events,making it difficult to study its effects, particularly in vivo, onany one system. Although this review focuses on its neuro-logical functions, most of what is known about IL-4 comesfrom studies of peripheral immune cells, such as macrophagesand lymphocytes. Therefore, in discussing the cellular targetsof this cytokine, we will extrapolate from those cell types whereappropriate.The earliest studies of IL-4 in macrophages showed that

it acted as an anti-inflammatory agent when administeredconcurrently or shortly after an inflammatory stimulus, andwas capable of downregulating the production of inflammatorycytokines such as TNF (35). IL-4 is not purely an anti-in-flammatory agent, however, as priming of macrophages withIL-4 followed by proinflammatory stimulation can resultin an enhanced inflammatory response (36). Studies in vivoshowed that chronic high dosage or transgenic overproductionof IL-4 results in accumulation of AAMFs, increased IFN-gexpression, decreased proinflammatory cytokine production,histiocytosis, erythrophagocytosis, extramedullary hemato-poiesis, and weight loss (37).These data suggest that the in vivo effects of IL-4 are

complex, well regulated, dependent on the local environment,and that they probably mediate different processes simulta-neously in different tissues. The situation is even more complexin the context of the brain, which is clearly affected by IL-4;however, little is known about the ability of this cytokine toaccess the parenchyma or the nature of its effects on target cells.Microglia and astrocytes within the CNS have been studiedwith regard to IL-4, but the possible role of IL-4 in directlystimulating neurons and oligodendrocytes is poorly under-stood.

Astrocytes

As mentioned earlier, BDNF production by astrocytes mightprovide a mechanism whereby IL-4 influences cognition (5).BDNF may not be the only participating factor, however, asIL-4 can also elicit astrocytic expression of other CNS growthfactors, such as nerve growth factor (38, 39). This function ofIL-4 is not unexpected, as it can also induce other growth andsurvival pathways in the periphery (40). Astrocytes clearlyrespond to IL-4, but their receptor expression and the factorsthat regulate receptor expression are not well understood. Inthe epileptic brain, astrocytes express high levels of IL-4Ra,but do not express the common g-chain (41), suggesting theymay signal through the type 2 complex (the more typicalreceptor for nonhematopoietic cells; Fig. 1). IL-4 can exertboth proinflammatory and anti-inflammatory effects on as-trocytes, depending on the treatment and timing paradigm. Inprimary mouse astrocytes, pretreatment with IL-4 decreasessubsequent production of NO and inducible NO synthaseprotein, as well as secretion of TNF upon LPS stimulation(38). Similarly, concurrent treatment of primary fetal humanastrocytes with IL-4 attenuates NO production by those cellswhen stimulated with IL-1b, TNF, or IFN-g (42). In anotherstudy, however, IL-1b–pretreated primary mouse astrocytesdemonstrated enhanced IL-6 production when subsequentlytreated with IL-4, whereas treatment with IL-10 and dexa-methasone yielded immunosuppressive effects. The samestudy showed that IL-1b induces astrocytic IL-4Ra expression

(43). Interestingly, both IFN-g and IL-4 can elicit neuro-protective phenotypes in astrocytes. Treatment with IFN-genhances the ability of astrocytes to clear extracellular gluta-mate (an excitatory neurotransmitter), an effect that is an-tagonized by IL-4 (44). However, conditioned medium fromIL-4–treated astrocytes is neuroprotective in a dose-dependentmanner, whereas the same is true for IFN-g at low doses only(44). The findings of the latter study thus point to a complexinterplay between these two canonical Th1 and Th2 cytokinesin the context of neuroprotection. Altogether, these findingsshow that astrocytes have a relationship to IL-4 that is com-plex and merits further study.

Microglia

Microglia are the brain’s equivalent of tissue-resident mac-rophages. Their lineage is similar to that of macrophages,although they engraft very early in development and maintaina self-renewing population throughout the life of the organ-ism (45). However, when certain conditions are met, usuallyinvolving damage, new microglia-like cells from the monocytelineage can be engrafted into the brain of an adult animal(46).Microglia respond comparably to macrophages in skewing

paradigms (M1 and the many variants of M2) (47, 48). Theseinclude expression changes of proteins such as YM1 andARG1, typical of IL-4–treated macrophages. Like macro-phages, microglia respond to IFN-g priming and subsequentstimulation by upregulating NO production through induc-tion of inducible NO synthase (49). Incubation with IL-4before priming with IFN-g or TNF, and subsequent stimu-lation with PMA, causes a dose-dependent decrease in NOproduction (49). Indeed, it has been shown that IL-4 exertsa neuroprotective effect via decreasing TNF and increasingIGF-1 (50). IL-4 also antagonizes IFN-g–driven MHCIIexpression (51). However, IL-4 alone, after long-term expo-sure, also induces MHCII expression (50). CD200, a micro-glial regulatory protein, is expressed on neurons in an IL-4–dependent fashion, providing a possible mechanism for IL-4–mediated regulation of microglial activation. Neurons fromIL-42/2 mice were found to be less effective than wild-typeneurons in attenuating an inflammatory response, a result thatwas linked to lower CD200 expression on the IL-42/2 neu-rons (52). Another interesting finding was that IL-4–activatedmicroglia can bias adult neural progenitor cells toward oli-godendrogenesis (53). In addition, IL-4 was found to induceCD11c on microglia in vitro, a marker typically associatedwith dendritic cells (54). All in all, it seems that microglia andmacrophages similarly respond to IL-4 signaling, and thatabsence of IL-4 heightens vulnerability to neuroinflammation.It remains unclear, however, whether IL-4 has a proin-flammatory role in microglial biology, as it does in macro-phages.

IL-4 in neurological pathology

IL-4 has a well-established role in the pathology of allergy andother immunological diseases, where it is secreted by T cellsto induce B cell activation and IgE class switching. Less wellstudied, but nevertheless also important, is its influence inother diseases, including neurological ones such as Alzheimer’sdisease (AD), multiple sclerosis (MS), and glioblastoma mul-tiforme (GBM).

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Inflammatory changes in the aging and AD brains

Aging in humans and rodents is accompanied by steady cog-nitive decline. Among the contributors to this decline is anincrease in baseline inflammation. The performance of agedmice in the MWM is impaired relative to that of younger adults,in correlation with proinflammatory changes in the hippo-campal (55) and global (56) transcriptome (57). Proinflam-matory cytokines, such as IL-1b, IL-6, and IL-18, are increasedin the aged hippocampus and are known to affect long-termpotentiation (LTP), a cellular mechanism of memory wherebythe strength of neuronal connections is modified (58–60).The effects of IL-4 in aging have been reported in only a few

publications, but the role of this cytokine in counteractinginflammatory changes is indisputable, and the increase incytokines such as IL-1b and IL-6 observed in aging animals isaccompanied by a decrease in hippocampal IL-4 (61). Thisdecrease is functional, and direct i.c.v. administration of IL-4rescues the LTP defects observed in aged mice (62). IL-4 canalso counter the effects of IL-1b on LTP when coadminis-tered i.c.v. (61). Interestingly, microglia become less sensitiveto IL-4 in aged mice and tend to activate more readily, withresulting impairment of LTP (63, 64). These experimentssuggest a potential role for IL-4 in countering age-relatedproinflammatory changes, although whether the inflamma-tion itself derives from a lack of IL-4 signaling is not known.The cognitive impairment seen in aged mice might be par-tially explained by the increase in proinflammatory cytokinesand a decrease in the amount of and sensitivity to the op-posing cytokine IL-4, which, in turn, disrupts LTP and im-pairs learning.Many of the same inflammatory processes that operate in

aging contribute to the pathology of AD, such as IL-1b–relatedinflammation (65, 66). IL-4 treatment can reverse certainaspects of AD pathology in animal models (Fig. 2), as shown,for example, by the finding that viral gene delivery of IL-4 tothe CNS of an AD mouse model alleviates several aspects ofthe disease (67).There is also a tendency toward microglial activation in AD.

Microglia tend to switch from M2- to M1-like activation asAD progresses (68). The microglial regulatory moleculesCD200 and CD200R are decreased in AD (69), leading tounchecked microglial activation. As described earlier, IL-4regulates CD200/CD200R expression (52, 70), and onepossible mechanism by which it exerts its effect in AD is bypromoting CD200R expression on microglia, helping to quelltheir pathological activation (71). In addition to negatinginflammatory mediators, IL-4 may confer direct benefit byinducing the IL-4–associated M2-type microglia, which havebeen shown in vitro to have superior amyloid-b clearancerelative to M1 microglia (72, 73). In line with this, admin-istration of amyloid-b–specific Th2 cells in the mouse modelof AD improves spatial memory, decreases microglial plaqueinvolvement, and reduces cerebral amyloid blood vessel pa-thology (74).

Role of IL-4 in MS

MS is a progressive demyelinating condition characterized bya relapsing and remitting course of neurological symptomssuch as blurred vision, impaired balance, and paresthesias. As itprogresses, MS can become increasingly debilitating and ul-timately fatal. MS is often studied in rodents with experimental

autoimmune encephalitis (EAE), an animal model for MS,which is induced in mice by adoptive transfer of CNS-reactiveT cells or active immunization with CNS Ags. Studies of theseverity of EAE in IL-42/2 mice relative to wild-type mice(75) point to a potentially protective role of IL-4 against theincidence and progression of MS.The IL-4R is highly expressed on perivascular macrophages

(76), pointing to the potential for IL-4 to regulate the mye-loid compartment in animals with EAE. Microglia may helpto protect the brain against autoimmunity by regulatingthemselves with local CNS-derived IL-4. Resting and EAE-derived microglia produce IL-4 and express Ym1 (an M2marker), whereas infiltrating macrophages in EAE produceNO (an M1 marker) (48). Interestingly, replacement of IL-42/2 bone marrow by wild-type bone marrow does not suf-fice to reduce EAE severity to wild-type levels, pointing to thepossibility of a brain-endogenous source of IL-4 (48). Fur-thermore, administration of skewed M2 cells can significantlyreduce EAE severity, even when injected after disease onset inrats (77) or i.c.v. into mice (78). The molecular signaling ofM2 cells was recently established further in the murine EAEmodel, and suggested that M2 cells can inhibit atypical EAEvia SOCS3 signaling (79). These findings demonstrate theimportance of myeloid skewing in MS, and suggest that IL-4might coordinate a beneficial M2 response.

GBM and IL-4

GBM is a devastating tumor with a 5-y survival rate of ∼3%(80). The role of IL-4 in cancer appears to differ from its role

FIGURE 2. A working model of IL-4 function in the subarachnoid space

after learning. After MWM training, T cells in the meninges become activated

by a yet unknown mechanism and produce IL-4. IL-4 then may skew men-

ingeal macrophages to M2, which have been shown to reverse cognitive defects

of immunosuppressed mice. IL-4 additionally affects astrocytes, although it is

unclear whether and how it crosses the BBB to do so. Other potential targets

include microglia and neurons, although data are lacking to conclusively

describe this response.

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in other neurological diseases, in that it manifests somewhatcontradictory protumor and antitumor effects depending onthe tumor and the tissue type (81). Interestingly, the majorityof GBM patient samples overexpress the IL-13Ra2 chain (82)and the IL-4Ra in culture (83, 84). In addition, GBM riskand outcome are altered by polymorphisms in these genes.There is a well-established inverse correlation between allergy,a disease process affected by IL-4, and GBM occurrence:individuals diagnosed with GBM are significantly less likelyto report allergies (85, 86). This observation is supported bythe finding that asthma-associated single nucleotide poly-morphisms in the il4r, il13, and stat6 gene loci are also in-versely correlated with occurrence of GBM (87, 88). Anotherstudy showed that certain polymorphisms in il4r correlate toimproved GBM mortality rates (89).These studies highlight the importance of IL-4 and IL-13 in

GBM biology, but the mechanism responsible for their effectis poorly understood. Early studies demonstrated that IL-4inhibits GBM xenograft growth in inducible IL-4ko celllines (90) and when administered s.c. (91) or retrovirally (92).Other studies use adenoviral delivery of IL-4 under a hypoxia-inducible promoter in various GBM xenograft lines, showingmarked regression of tumor growth and selective lysis ofhypoxic cells after viral treatment (93, 94). IL-4 is typicallythought to aid in tumor control by blocking angiogenesis (90,95) or recruiting eosinophils (96, 97).As tumors progress, macrophages become skewed from a

proinflammatory M1 to a tumor-promoting M2 phenotype.M2 macrophages support tumor growth and survival, induc-ing angiogenesis (through production of vascular endothelialgrowth factor), creating an immunosuppressive environment,and encouraging invasiveness and metastasis (98, 99). In anonbrain cancer model, IL-4 together with IL-10 and vascularendothelial growth factor are crucial to generation of theproinvasive M2 myeloid skew, and inhibition of IL-4Ra invivo blocks macrophage polarization (100). Thus, IL-4 func-tion in GBM might be dichotomous, being used by the tumorto create AAMFs, but toxic when administered directly.

ConclusionsThese studies collectively illustrate a crucial role for IL-4 inthe regulation of brain immunity, with measureable down-stream effects on spatial learning/memory and neurogenesis,and with implications for neurological disorders. From thedata reviewed in this article, it is tempting to assume that an“alternative” IL-4–driven activation of the immune systemsupports brain function, whereas molecules with classic“proinflammatory” signals hinder it. This view may, however,be an oversimplification of complex neuroimmune interac-tions taking place in boundaries of the brain and in the brainparenchyma. Although proinflammatory cytokines have beenimplicated in the detrimental effects of sickness behavior,aging, and autoimmunity, it is likely that a proper balance inperipheral and brain immunity is required for optimal brainperformance. In fact, certain cytokines associated with clas-sical inflammation are required for many aspects of vital CNSfunction such as synaptic scaling through glial TNF (101) andthe role of IL-6 in ensuring functional LTP in the hippo-campus (102).In times of stress and disease, the delicate balance in brain

immunity is altered, with proinflammatory molecules pro-

duced to a high degree in response to a potential threat (28).Production of IL-4 by meningeal T cells and other cell typescould therefore be viewed in terms of an evolutionary adap-tation to restore balanced CNS function and cognition. Newmolecular and genetic tools that target IL-4, IL-13, and theirreceptors in specific cell types will advance the field and fur-ther our understanding on the precise roles of T cell-derivedand non-T cell-derived IL-4 in the regulation of brain func-tion.Although replacing or even directly altering CNS cells

represents a substantial technical challenge, in part because ofthe BBB, the immune system is more easily targeted by drugsand can even be replaced by means of bone marrow trans-plantation. Therefore, a better understanding of the effects ofthe immune system on CNS function will open new thera-peutic avenues for diseases that have traditionally been ap-proached as purely neurological, but that have important andtreatable immune components (103).

AcknowledgmentsWe thank Shirley Smith and Nicola Watson for editing the manuscript. We

thank the members of the Kipnis laboratory for valuable comments during

multiple discussions of this work.

DisclosuresThe authors have no financial conflicts of interest.

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