Ad ances in unde s anding molecula egula ion o
inna e immune memo y
Jo ge Domínguez-And és
1,2,a
, S ephanie Fanucchi
3,4,a
,
Leo A. B. Joos en
1,2,5
, Musa M. Mhlanga
3,6
and
Mihai G. Ne ea
1,2,7
Abs ac
The epigene ic and unc ional ep og amming o immune genes
du ing induc ion o ained immuni y is accompanied by he
me abolic ewi ing o cellula s a e. This memo y is induced in he
hema opoie ic niche and p opaga ed o daugh e cells, gene a ing
epigene ically and me abolically ep og ammed inna e immune
cells ha a e g ea ly enhanced in hei capaci y o esol e
in lamma ion. In pa icula , hese cells show accumula ion o
H3K4me3 and H3K27Ac epigene ic ma ks on mul iple immune
gene p omo e s and associa ed enhance s. Howe e , he
mechanism go e ning how hese epigene ic ma ks accumula e a
disc e e immune gene loci has been poo ly unde s ood, un il now.
He e, we discuss some ecen ad ances in he egula ion o
ained immuni y, wi h a pa icula ocus on he mechanis ic ole o
a no el class o long non-coding RNAs in he es ablishmen o
epigene ic ma ks on ained immune gene p omo e s.
Add esses
1
Depa men o In e nal Medicine and Radboud Cen e o In ec ious
Diseases (RCI), Radboud Uni e si y Nijmegen Medical Cen e, Gee
G oo eplein 8, 6500HB, Nijmegen, he Ne he lands
2
Radboud Ins i u e o Molecula Li e Sciences (RIMLS), Radboud
Uni e si y Medical Cen e , 6525, GA, Nijmegen, he Ne he lands
3
Di ision o Chemical, Sys ems & Syn he ic Biology, Depa men o
In eg a i e Biomedical Sciences, Facul y o Heal h Sciences, Ins i u e
o In ec ious Disease & Molecula Medicine, Uni e si y o Cape Town,
Cape Town, Sou h A ica
4
Gene Exp ession and Biophysics G oup, ERA, CSIR Biosciences,
P e o ia, Sou h A ica
5
Depa men o Medical Gene ics, Iuliu Ha ieganu Uni e si y o Med-
icine and Pha macy, 400349, Cluj-Napoca, Romania
6
Gene Exp ession and Biophysics Uni , Ins i u o de Medicina Molec-
ula , Faculdade de Medicina Uni e sidade de Lisboa, Lisbon, Po ugal
7
Depa men o Immunology & Me abolism, Li e and Medical Sci-
ences Ins i u e (LIMES), Uni e si y o Bonn, 53115 Bonn, Ge many
Co esponding au ho s: Domínguez-And és, Jo ge. (jo ge.domi-
[email p o ec ed]); Fanucchi, S ephanie. (pa ucchie e@
mhlangalab.o g)
a
These au ho s con ibu ed equally.
Cu en Opinion in Cell Biology 2020, 63:68–75
This e iew comes om a hemed issue on Cell Signalling
Edi ed by And ea Ablasse and Je emy W. Tho ne
Fo a comple e o e iew see he Issue and he Edi o ial
A ailable online 25 Janua y 2020
h ps://doi.o g/10.1016/j.ceb.2019.12.006
0955-0674/© 2020 The Au ho s. Published by Else ie L d. This is an
open access a icle unde he CC BY-NC-ND license (h p://
c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
Keywo ds
Monocy es, Mac ophages, Inna e memo y, T ained immuni y, Epige-
ne ics, Me abolism, TADs, lncRNA, S em cells.
In oduc ion
A undamen al elemen in he su i al o o ganisms
con on ed wi h con inuous exposu e o po en ially pa h-
ogenic mic oo ganisms is he p esence o a s ong and
dynamic de ense sys em. Two di e en le els o immune
esponse a e ecognized: inna e and adap i e. The i s
one is ega ded as he i s line o de ense agains he en y
o mic obes and he apid elimina ion o hose ha ha e
al eady pene a ed he o ganism be o e hey cause in ec-
ion. This esponse p o ides nonspeci ic p o ec ion and is
based on he ecogni ion o e olu iona ily p ese ed
s uc u es ound in he pa hogens known as pa hogen-
associa ed molecula pa e ns ha ac as ligands o he
pa e n ecogni ion ecep o s, exp essed by he cells o he
inna e immune sys em. Inna e immune cells wi h he
capaci y o ac as an igen-p esen ing cells such as mac o-
phages and dend i ic cells p ocess and p esen mic obial
pep ides o he adap i e b anch o he immune sys em,
p o iding an igen-speci ic p o ec ion agains ein ec ion.
App oxima ely 400 million yea s ago, du ing he Camb ian,
e eb a es de eloped mechanisms o gene a e di e si y
ha depend on ecombina ion o he VDJ elemen s and
he p esence o Rag1 and Rag2 genes. The genomic
ecombina ion p o ided by hese sys ems allows he e o-
lu ion o he immune sys em o e eb a es and he
eme gence o genes ela ed wi h he adap i e immune
sys em o mammals. Based on hese mechanisms, e e-
b a es ha e de eloped he capaci y o ‘ emembe ’ he
an igen o pa hogen wi h which hey ha e had con ac ,
en ailing a la ge e olu iona y ad an age.
Inna e immune memo y in e eb a es:
ained immuni y
I is inc easingly e iden ha he inna e immune e-
sponses a e a mo e sophis ica ed han he p e iously
A ailable online a www.sciencedi ec .com
ScienceDi ec
Cu en Opinion in Cell Biology 2020, 63:68–75 www.sciencedi ec .com
held iew in which hey a e p imi i e esponses ha a e
igge ed each ime in he same ashion. An inc easing
amoun o e idence shows ha s imula ion o he cells
igge s a unc ional ep og amming in cells o he
inna e immune sys em, such as monocy es and na u al
kille (NK) cells, acili a ing a as e and enhanced
esponse o seconda y challenges wi h he same o
o he s imuli [1]. This inna e immunological memo y
in esponse o nonspeci ic s imuli has been e med
‘ ained immuni y’ [2]. Long- e m epigene ic and
me abolic ep og amming o monocy es and mac o-
phages is necessa y o p o ide inc eased esponsi eness
agains sys emic he e ologousin ec ionsin e eb a es
[1] and can also be induced in al eola mac ophages by
a espi a o y i al in ec ion, hanks o he local elease
o IFN
g
by e ec o CD8þlymphocy es in mice [2].
Exposu e o human NK cells o Candida albicans-
induced me abolic ep og amming in hese cells
inc easing hei p oduc ion o pe o in [3]. The po-
en ial o induc ion o inna e immune memo y is no
es ic ed o mic obial ligands. Endogenous molecules,
such as oxLDL, glucose o u ic acid in high concen-
a ionsa ealsoable o igge hesemechanismsand
lead o he de elopmen o ch onic in lamma o y e-
sponses such as hose seen in pa ien s wi h diabe es,
a he oscle osis, gou , o cance [4e6]. T ained immu-
ni y has also been linked wi h physiological p ocesses
such as human p egnancy, whe e NK cells suppo
ascula sp ou ing and imp o ed placen a ion [7].
No el esea ch also sugges s ha he ea u es o
ained immuni y a e no s ic ly es ic ed o immune
cellsbu also oo he cellssuchas ib oblas so s omal
cells [8], epi helial cells [9] and ha he long- e m
consequences o ained immuni y a e ansmi ed
h ough du able modi ica ions in he epigene ic land-
scapeo hecellso hehema opoie icniche[10,11].
These nonimmune cells exp ess ecep o s o se e al
in lamma o y media o s, which enables hem o adjus
o he in lamma o y milieu [3e5]. Mo eo e , s omal
and epi helial cells a e also equipped wi h he e-
cep o s o sense whe he he epi helial ba ie is
b eached and, in u n, ac i ely ec ui he immune cells
[6]. T ained immuni y also p o ides an explana ion o
he he e ologous e ec s o accines: he capaci y o
some accines o p o ide immune p o ec ion agains
in ec ions o he han he speci ic a ge , wi h educed
all-cause mo ali y [12,13].
The immune pa hways leading o epigene ic
changes
The induc ion o ained immuni y elies on he ac i-
a ion o in acellula elemen s, such as he Ak -
mTOReHIFe1
a
pa hway, wha leads o he ec ui -
men o ansc ip ional egula o s o immune p ocesses,
such as NF-kB and nuclea ac o o ac i a ed T cells
(NFAT) [7]. Du ing p ima y s imula ion, he ac i a ion
o gene ansc ip ion is accompanied by he deposi ion
o speci ic his one ace yla ion and me hyla ion ma ks,
such as H3K4me3 o H3K27ac, gene egula o y ele-
men s ha egula e he exp ession o p oin lamma o y
ac o s. This p ocess inc eases he accessibili y o he
DNA o he ansc ip ional machine y and egula o y
elemen s, p omo ing and acili a ing enhanced an-
sc ip ion [14](Figu e 1). Challenge o monocy es wi h
b
-glucan also leads o he en ichmen o ace yla ion o
his one 3 lysine 27 (H3K27ac), monome hyla ion o
his one 3 lysine 4 (H3K4me1), ime hyla ion o his one
3 lysine 4 (H3K4me3), and inc eased DNase I accessi-
bili y ac oss speci ic loci o monocy es. The deposi ion
o H3K27ac ma ks is o en pa alleled by ha o
H3K4me1. The e o e, e en i a conside able po ion o
he H3K27ac ma ks a e los du ing cell di e en ia ion,
he emaining H3K4me1 ma ks he i ably main ain an
open con o ma ion o he ch oma in and as a conse-
quence emain sensi i e o clea age by DNase I [15].
The en ichmen o H3K4me3 a he p omo e s o loci
encoding p oin lamma o y genes plays a cen al ole in
di e en expe imen al models o inna e immune
memo y, such as
b
-glucan s imula ion o he induc ion
o ained immuni y by oxLDL in human cells [16]. In
line wi h his, H3K4me3 en ichmen a he p omo e s o
genes encoding TNF
a
and IL-6 is necessa y o he
inc eased esponsi eness obse ed a e he accina ion
o heal hy olun ee s wi h bacille Calme e-Gue
´ in
(BCG) [17]. In con as , he ea men wi h E. coli-
de i ed lipopolysaccha ide delays he es ablishmen o
all hese ch oma in ma ks in human cells [14]. This
ailu e o deposi ac i e his one ma ks a p omo e s o
p oin lamma o y genes is behind he lack o espon-
si eness o seconda y s imula ion (also known as
immune ole ance) in esponse o a seconda y challenge
wi h lipopolysaccha ide [14]. Epigene ic changes un-
de lying ch onic p oin lamma o y gene exp ession in
si ua ions o hype glycemia ha e been ela ed wi h a
pe sis en , long-las ing H3K4me1 in p oin lamma o y
genes [18]. Al hough hese s udies ha e ocused on
commonly s udied his one ma ks, such as H3K27Ac and
H3K4me3, he e a e a la ge numbe o di e en his one
ma ks ha may ac in a combina o ial manne o ac i a e
o ep ess ansc ip ion. Clea ly, u u e s udies a e
equi ed o in es iga e how ained immuni y in luences
he deposi ion o o he ch oma in modi ica ions (e.g.
H3K9 and H3K14 ace yla ion on ac i e enhance s and/
o p omo e s, and me hyla ion o H3K36 in ansc ibed
gene bodies). This insigh is necessa y o p o ide
addi ional insigh in o how he longe i y o epigene ic
memo y is es ablished.
The in eg a ion o me abolic pa hways and
epigene ic changes
The changes obse ed in he epigene ic landscape a e
concu en wi h he me abolic ep og amming o he
cells. The s imula ion o inna e immune cells wi h mi-
c obial o endogenous ligands in ol ed in he induc ion o
Molecula egula ion o ained immuni y Domínguez-And és e al. 69
www.sciencedi ec .com Cu en Opinion in Cell Biology 2020, 63:68–75
Figu e 1
Cu en Opinion in Cell Biology
The molecula basis o ained immuni y is unde pinned by he epigene ic ep og amming o immune genes. Inna e immune cells (such as
ci cula ing monocy es and mac ophages) exposed o s imuli (including
b
-glucan, bacille Calme e-Gué in -BCG- and oxLDL) a e epigene ically
ep og ammed. As a consequence o his, upon exposu e o a seconda y s imulus, immune genes a e mo e obus ly ansc ibed. This p ocess is
egula ed by a no el class o lncRNAs, called immune p iming lncRNAs (IPL), which a e up egula ed by he ini ial s imulus. IPLs di ec ly in e ac wi h
WDR5, o di ec MLL1 p oximal o immune genes, acili a ing he deposi ion o H3K4me3 a he p omo e s o immune genes. In his way, immune genes
a e mo e obus ly ansc ibed upon seconda y in ec ion/s imulus in ained immune cells. lncRNAs, long non-coding RNAs, MLL1, mixed lineage leukemia
p o ein 1; WDR5, WD epea -con aining p o ein 5.
70 Cell signalling
Cu en Opinion in Cell Biology 2020, 63:68–75 www.sciencedi ec .com
inna e immune memo y mechanisms al e s he gene ic
landscape o me abolic egula o s. In his sense, di e en
genes in ol ed in glycolysis, ica boxylic acid (TCA)
cycle, glu aminolysis, and he choles e ol pa hway a e
quickly up egula ed a e s imula ion, causing changes in
he le els o in acellula me aboli es in mice and human
[8e10]. Va ia ions in he le els o in acellula me abo-
li es de i ed om hese pa hways al e he unc ionali y
o enzymes esponsible o ‘w i ing’, ‘e asing’ o ‘ eading’
his one and DNA modi ica ions ha al e he epigene ic
landscape o he inna e immune cells. In his ega d,
ace yl-CoA de i ed om glycolysis and glu aminolysis is
able o ac as a dono o ace yl g oups o ace yla ion o
his ones [19]. Accumula ion o ci a e acili a es he
p oduc ion o soluble ac o s ha p omo e in lamma ion
such as de i a i es o a achidonic acid o ni ic oxide [20].
Inc eased le els o i acona e a e mic obial s imula ion is
ela ed wi h a dec ease in he deposi ion o epigene ic
ma ks in monocy es, leading o he de elopmen o
immune ole ance [21]. The p esence o
a
-ke oglu a a e
is undamen al o he ac i i y o he en-ele en ans-
loca ion (TET) p o eins, leading o he elimina ion o
DNA ep esso ma ks [22]. These TET p o eins a e
in ol ed in he emodeling o he DNA me hyla ion
landscape o cells om he hema opoie ic niche in he
bone ma ow and hus a e c ucial o he long- e m
ep og amming o sys emic inna e immune esponses
a e
b
-glucan o BCG challenge in mice [10,11].
Al hough his ela ionship is ye o be shown in humans,
his s ongly sugges s ha he TET p o eins will ha e a
signi ican impac on inna e immune cell ep og amming.
His one lysine deme hylases o he JmjC and JmjD amily
also need
a
-ke oglu a a e as a co ac o o induce deme-
hyla ion [23]. S-adenosyl me hionine, o med om
adenosine and me hionine h ough he enzyme me hio-
nine adenosyl ans e ase, is a common cosubs a e
in ol ed in he ans e o me hyl g oups and necessa y o
he ac ions o his one and DNA me hyl ans e ases
(DNMTs) [24]. Succina e induces he s abiliza ion o he
ansc ip ion ac o HIF1
a
, which igge s an in acellula
pa hway ha leads o he accumula ion o H3K4me3 and
H3K27ac in he p omo e egions and egula o y a eas o
p oin lamma o y genes h ough a pa hway ha also in-
ol es he ac i a ion o mTOR and Ak [25,26]. Fo i s
pa , uma a e an agonizes he hyd oxyla ion eac ion
necessa y o HIF1
a
deg ada ion, con ibu ing o he s a-
biliza ion o his ac o and inhibi ion o he ac i i y o he
KDM5 amily o his one deme hylases [27]. This en-
hances he long- e m ep og amming o he epigene ic
landscape o monocy es, skewing hem owa d a ained
pheno ype ha a o s an inc eased esponsi eness a e
seconda y s imula ion. The epigene ic p o iles o mono-
cy es and mac ophages challenged by di e en ligands
ha induce inna e immune memo y, such as
b
-glucan,
BCG, oxLDL, o u ic acid, show close simila i ies among
each o he a a mechanis ic le el [6,10,11,15].
The ole o lncRNAs and 3D nuclea
a chi ec u e in ained immuni y
Al hough i is clea ha immune genes and associa ed
enhance s a e epigene ically ep og ammed du ing
ained immuni y, i is poo ly unde s ood how epige-
ne ic emodeling enzymes (such as mixed lineage leu-
kemia p o ein 1 [MLL1]) a e disc e ely a ge ed o
ained immune genes and enhance elemen s. Clea ly,
gene egula o y mechanisms acili a e he p ecise
a ge ing o hese ch oma in emodele s, a he co ec
spa io empo al loca ion and in a con ex -speci ic
manne .
By egula ing immune gene ansc ip ion, he noncoding
po ion o he genome has been shown o play an in e-
g al egula o y ole in he egula ion o in lamma o y
p ocesses [28]. I appea s ha a signi ican po ion o
he genome is ansc ibed in o a highly di e se amily o
RNAs, ha ange in size om >200 n o mo e han 10
Kbp in leng h. Many o hese so-called long noncoding
RNAs (lncRNAs) a e key modula o s o gene egula ion
ha ac a a ious s ages o he ansc ip ional p og am
o ei he ampli y o ep ess gene ac i i y [29]. lncRNAs
a e dis inc om p o ein coding RNAs, in ha hey may
ac in cis o egula e genes in hei su ounding genomic
neighbo hood. As a consequence, e y ew copies o
lncRNAs (e en 1 o 2 copies pe cell) may signi ican ly
in luence gene egula ion. Howe e , owing o echnical
challenges in hei de ec ion and unc ional cha ac e -
iza ion, i can be di icul o de e mine whe he lncRNA
ansc ip s a e indeed unc ional and no simply he by-
p oduc o ansc ip ional noise [30]. The e o e, despi e
he ac ha housands o lncRNAs ha e been iden i-
ied, he comple e molecula unc ion o only a ew
lncRNAs has been desc ibed. Se e al well-designed
s udies ha e e ealed ha lncRNAs can se e as unc-
ional ansc ip s ha play an impo an ole in he
de elopmen o disease s a es, including cance , in ec-
ious disease, and in lamma ion [31]. These s udies
e eal ha lncRNAs can ac in cis o ans ia di e se
mechanisms ha includes ac ing as sca olds, decoys,
and ec ui e s o ch oma in emodele s (ex ensi ely
e iewed in [29,31]). Fo example, ca e ul mechanis ic
analysis e ealed ha lincRNA-Cox2 in e ac s wi h
hnRNPA2/B1 and hnRNP-A/B o ep ess a la ge numbe
o immune genes [32]. LncRNAs such as NeST and
HOXA dis al ansc ip an isense RNA (HOTTIP) ha e
been con incingly shown o in e ac wi h WD epea -
con aining p o ein 5 (WDR5) and di ec MLL1 o
a ge genes in cis, allowing he deposi ion o H3K4me3
a he p omo e s o IFNG and he HOXA genes,
espec i ely [28,33].
The olding o ch oma in in h ee dimensions has a
signi ican impac on gene egula ion [34,35]. High-
h oughpu ch omosome con o ma ion cap u e and
associa ed echniques (ch oma in in e ac ion analysis by
Molecula egula ion o ained immuni y Domínguez-And és e al. 71
www.sciencedi ec .com Cu en Opinion in Cell Biology 2020, 63:68–75
pai ed-end ag sequencing (Hi-C, and so on) ha e
e ealed ha ch oma in is olded in o DNA loops, which
a e spa ially seg ega ed in o opologically associa ing
domains [34]. Ch omosomal looping wi hin opologi-
cally associa ing domains has been shown o b ing
dis ally loca ed lncRNAs and hei p o ein pa ne s
adjacen o a ge genes o egula e hei ansc ip ional
ac i a ion. Fo example, HOTTIP has been shown o
use 3D ch oma in opology o di ec he WDR5/MLL1
complex p oximal o he HOXA genes [33].
Figu e 2
Cu en Opinion in Cell Biology
An o e iew o he in e play be ween me abolism and epigene ics du ing ained immuni y.
b
-glucan/dec in-1 signaling ac i a es calcium-
dependen NFAT signaling, o induce he ansc ip ion o he IPLs esul ing in he H3K4me3 epigene ic ep og amming o immune gene p omo e s.
Toge he wi h enhance elemen s, IPLs a e able o access a ge genes ia 3D ch omosomal looping. Concu en ly, he e is he ac i a ion o mTOR-HIF1
a
signaling, which al e s he ac i i y o di e en in acellula pa hways. As a consequence, he e is an inc ease in he supply o me aboli es and co ac o s
ha a e essen ial o consolida e he epigene ic changes ha a e causal o he ained immuni y pheno ype. IPLs, immune gene p iming lncRNAs.
72 Cell signalling
Cu en Opinion in Cell Biology 2020, 63:68–75 www.sciencedi ec .com

As hese ac o s a e cen al o epigene ic egula ion, we
ecen ly explo ed he con ibu ion o lncRNAs and 3D
nuclea a chi ec u e in he egula ion o ained im-
muni y in human cells [11]. Using a no el bio-
in o ma ic pipeline, we iden i ied se e al lncRNAs
which we named immune gene p iming lncRNAs
(IPLs) [36].Onecandida eIPL,whichweha enamed
ups eam mas e lncRNA o he in lamma o y chemo-
kine locus, engaged in ch omosomal con ac s wi h he
p omo e s o he ELR þCXCL chemokines (IL-8,
CXCL1, CXCL2, and CXCL3). Using loss- and gain-o -
unc ion expe imen s, we demons a ed ha ups eam
mas e lncRNA o he in lamma o y chemokine locus
uses 3D nuclea opology o di ec he WDR5/MLL1
complex ac oss he CXCL chemokine p omo e s. This
enables he H3K4me3 epigene ic p iming o hei
p omo e s be o e ansc ip ional ac i a ion. Impo -
an ly, his mechanism was sha ed wi h o he key
ained immune genes, such as IL-6 and IL1
b
.A he
ansc ip ional le el, exposu e o monocy es o
b
-
glucan esul ed in he an NFAT-media ed inc ease in
he exp ession o IPLs, which in u n esul ed in he
epigene ic ep og amming o inna e immune genes
(Figu e 2). The p omo e s o IPLs con ain mul iple
ansc ip ion ac o binding mo i s, o example, STAT,
AP-1, and RELA. This sugges s ha di e gen s imuli
ha ac i a e dis inc signal ansduc ion cascades may
con e ge on he ac i a ion o IPLs. This may explain
how di e en aining agen s (e.g.
b
-glucan, oxLDL,
BCG) ha ac i a e di e en ecep o s a e able o
induce IPL exp ession and epigene ically ep og am
immune genes.
Enhance RNAs and ained immuni y
Enhance s may also be ansc ibed in o lncRNAs called
enhance RNAs (eRNAs) which a e ypically exp essed
in a cell-speci ic manne . In se e al ins ances, he an-
sc ip s ha a ise om enhance s ha e been shown o play
a signi ican ole in he egula ion o ch omosomal looping
and issue-speci ic a ge gene ansc ip ion [37]. Fo
example, in sepa a e s udies, eRNAs ha e been shown o
in e ac wi h componen s o he media o complex o Yin
Yang 1 o egula e ch omosomal con ac s be ween a ge
genes and enhance s [37,38]. Recen ly, eRNAs ha e been
shown o in e ac wi h p300 and cyclic adenosine
monophospha e esponse elemen ebinding p o ein,
which a e wo highly conse ed p o eins ha possess
his one ace yl ans e ase ac i i y [39]. The s udy
e ealed ha eRNAs bind o p300 and cyclic adenosine
monophospha e esponse elemen ebinding p o ein,
which in u n s imula es ca aly ic his one ace yl-
ans e ase ac i i y and esul s in ansc ip ional ac i a-
ion. The e o e, i is easonable o specula e ha by
egula ing his one ace yla ion and looping a key en-
hance s, eRNAs may play an in eg al ole in ained
immune esponses.
Conclusions and u u e pe spec i es
In i o s udies ha e shown he pe sis ence o epigene ic
BCG-inducedmemo yinmiceup o20weeks[12] a e
accina ion and up o a mon h in humans accina ed wi h
BCG [13]. A p esen , i emains unknown whe he his
enhanced p o ec ion a e se e al yea s is also accompa-
nied by epigene ic memo y. Recen s udies ha e
demons a ed ha epigene ic memo y is induced in he
hema opoie ic niche, which is hen p opaga ed o
daugh e cells [10,11]. In his way, long- e m inna e
immune memo y may be es ablished. Wha is less clea is
he con ibu ion o lncRNAs and enhance s o he gen-
e a ion and main enance o long- e m memo y. We
specula e ha hema opoie ic s em cells (HSCs) may be
ained in an IPL-dependen manne , simila o wha
occu s wi hin ci cula ing monocy es ained wi h
b
-
glucan [40]. The pa hways ha up egula e he IPLs, may
also lead o he ansc ip ion o enhance elemen s,
which would in u n inc ease hei accessibili y and
ace yla ion. These epigene ic changes would hen be
ansmi ed om HSCs and p ogeni o s o he ma u e
monocy es and mac ophages. The e o e, deciphe ing he
unc ion o hese noncoding elemen s will be c i ical o
elucida e he exac mechanism o how ained immuni y
is es ablished.
The e is s ong e idence ha o he ‘classes’ o lncRNA
may egula e aspec s o immune memo y. By me hyl-
a ing cy osines (m5C) in CpG- ich sequences,
DNMTs a e able o induce ansc ip ional ep ession.
Se e al s udies e eal ha all h ee majo DNMTs can
bind and be egula ed by lncRNAs [14]. The e o e, i is
emp ing o specula e ha he e may be a class o
immune ‘supp essing’ lncRNAs ha may di ec ly
oppose IPL ac i i y by guiding DNMTs o a ge genes
acili a ing hei supp ession. Nume ous s udies o e
he las ew yea s ha e e ealed ha lymphocy es also
exp ess unique p o iles o lncRNAs ha coo dina e he
de elopmen and ac i a ion s a e o bo h T and B cells.
Fo example, he IFN
g
locus is epigene ically egula ed
by NeST, a WDR5-in e ac ing lncRNA [15]. IPLs
acili a e he obus ansc ip ion o inna e immune
genes [36]. The e o e, i is highly likely ha IPLs
egula e obus ly ansc ibed lymphocy e-speci ic genes
ha unde lie adap i e immune esponses.
Collec i ely, hese s udies ha e e ealed nume ous
me abolic and epigene ic a ge s ha could po en ially
be a ge ed o ei he induce o inhibi ained
immuni y. This would pe mi he abili y o enhance he
ac i i y o he inna e immune sys em in si ua ions in
which immune esponsi eness o an indi idual is
comp omised, such as in pa ien s who de elop immune
pa alysis a e sepsis, o people su e ing om immu-
node iciencies, AIDS, o ce ain ypes o cance . On he
o he hand, he inhibi ion o he mechanisms in ol ed
in he induc ion o ained immuni y would imp o e
Molecula egula ion o ained immuni y Domínguez-And és e al. 73
www.sciencedi ec .com Cu en Opinion in Cell Biology 2020, 63:68–75
he ou come in diseases cha ac e ized by excessi e
in lamma ion, such as a he oscle osis, diabe es, o in-
lamma o y bowel disease, amongs o he s. The de el-
opmen o new ma e ials such as nanopa icles,
polyme s, and sup amolecula sys ems, ha suppo he
design o new he apeu ic s a egies o modula e he
me abolic and epigene ic b anches o ained immuni y,
is becoming a eali y [41,42] and gua an ees exci ing
de elopmen s in his ield in he upcoming yea s.
Au ho con ibu ions
J.D.A and S$F w o e he o iginal d a . S.F. p epa ed he
igu es. L.A.B.J., M.M.M, and M.G.N. supe ised he
whole p ocess and made e isions.
Con lic o in e es s a emen
No hing decla ed.
Acknowledgemen s
M.G.N. was suppo ed by a Spinoza G an o he Ne he lands O ganiza ion
o Scien i ic Resea ch. L.A.B.J. was suppo ed by a Compe i i eness
Ope a ional P og am g an o he Romanian Minis y o Eu opean Funds
(HINT, ID P_37_762; MySMIS 103587). M.M.M. esea ch is suppo ed by
a Depa men o Science and Technology Cen e o Compe ence G an , an
SA Medical Resea ch Council SHIP g an , and a CSIR Pa liamen a y G an ,
all o M.M.M, and M.M.M. is a Chan Zucke be g In es iga o o he Chan
Zucke be g Ini ia i e.
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