Advances in understanding molecular regulation of innate immune memory

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. Re e ences Pape s o pa icula in e es , published wi hin he pe iod o e iew, ha e been highligh ed as: * o special in e es 1. 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