전신 자가면역질환에서 여포 보조 t세포의 위상 · 2013-03-07 · 포(dendritic...

© 2013 Hanyang University College of Medicine 1http://www.e-hmr.org

The Niche of Follicular Helper T Cells in Systemic Autoimmune Diseases Eunkyeong Jang1, Jeehee Youn2 1Institute of Biomedical Science; 2Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul, Korea

서 론

우리몸에는외부감염원으로부터우리몸을보호하는방어체계,즉면역계통(immunesystem)이발달되어있다.면역계통구성요소중하나인항체는병원체에감염되었을때이들을중화하거

나옵소닌화(opsonization)하거나보체계를동원해용해하는방식

으로제거하여우리몸을방어하는아주중요한체액성효과물질

이다.하지만대부분의면역요소가양면성을갖고있듯이,때로는항체가우리몸의조직이나장기를파손하는작용을하기도한다.항체에의한이런과민반응은미생물이나알레르겐이외에도자기몸의구성성분에의해유발되기도한다.후자와같은경우를자가항원(autoantigen)에반응하는자가항체(autoantibody)의존적인

“자가면역(autoimmunity)”상태라할수있으며,많은전신자가면

역질환(systemicautoimmunedisease)에서그런현상을찾아볼수있다.자가항체는표적자가항원이분포한조직에침윤되어보체및Fc수용체(FcR)를가진선천면역세포를활성화하여염증반응

을유발한다(제2형과민반응).또는혈액속에서항원과면역복합

체(immunecomplex)를구성하여혈관벽등에침윤되어제3형과민성염증반응을일으킨다.그러므로자가항체의생성기전을파악하는것이이런체액성자가면역질환의발병기전을이해하고조절하는데필요하다.우리면역계통은자기몸의구성요소에는반응을하지않도록

고안되어있다.이런면역적자가관용(immunologicself-tolerance)현상을유지하기위해정상인에서는다양한기전이작동되고있다.

Hanyang Med Rev 2013;33:1-9http://dx.doi.org/10.7599/hmr.2013.33.1.1

pISSN 1738-429X eISSN 2234-4446

Production of thymus-dependent antibodies by autoreactive B cells requires help from T cells. Follicular helper T (Tfh) cells are a unique lineage of CD4+ T subsets present in the fol-licles of peripheral lymphoid tissues which functions primarily to provide help to cognate B cells. Within germinal centers Tfh cells stimulate germinal center B cells to undergo affin-ity maturation, Ig class switching, and differentiation to memory B cells and plasma cells. Proposals that activity of Tfh cells is crucial for long-lived humoral autoimmunity are sup-ported by the correlation of numbers and/or functions of Tfh cells with disease activity in many autoimmune disorders. In this review, we discuss recent findings regarding Tfh cell development and function. In addition, we discuss putative roles of Tfh cells in the patho-genesis and highlight the potential of Tfh cells as therapeutic targets in autoimmune dis-eases.

Key Words: T-Lymphocytes, Helper; Autoimmune Diseases; Immunity, Humoral; Germinal Center

전신 자가면역질환에서 여포 보조 T세포의 위상 장은경1·윤지희2

한양대학교 의과대학 1의과학연구소, 2해부·세포생물학교실

Correspondence to: Jeehee Youn우133-791 서울시 성동구 왕십리로 222, 한양대학교 의과대학 해부 ·세포생물학교실 Department of Anatomy and Cell Biology, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea Tel: +82-2-2220-0604 Fax: +82-2-2281-7841 E-mail: [email protected]

Received 21 November 2012Revised 6 January 2013Accepted 14 January 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom-mons.org/licenses/by-nc/3.0) which permits un-restricted non-commercial use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.

Hanyang Med Rev 2013;33:1-92 http://www.e-hmr.org

Eunkyeong Jang, et al. • The Niche of Follicular Helper T Cells in Systemic Autoimmune DiseasesHMR

하지만여러유전적또는환경적요인에의해이런기전이와해되어자가반응적림프구가과다발생하거나아니면비정상적인수준으

로활성화되어적응면역반응이시작되면결국자가항체의과다생성을초래하는최종단계로이어진다.항체생성경로는T-비의존적

(T-independent,TI)경로와T-의존적(T-dependent,TD)경로로나눌수있다.전자와는달리,후자는단백질항원에대한항체가친화도성숙과클래스전환(classswitch)을겪으며생성되는경로

일뿐아니라장기기억기전을동반하는데,이과정에항원특이성

을공유하는T세포의도움이절대적으로필요하다.따라서TI항체

보다는TD항체가만성적전신자가면역질환의발병에좀더중요한역할을한다고할수있다.

TD항체의생성과정에서B세포도우미로작용하는세포중가장대표적인니치(niche)를구성하는세포가바로여포보조T(fo-llicularhelperT,Tfh)세포이다.이세포는2000년에처음으로사람편도에서동정되었는데,다른보조T세포와는달리여포귀환수용체인CXCR5의발현도가높아여포로들어갈수있고B세포

의활성화를보조하는역할을하기때문에그리이름이붙여지게되었다[1,2].그러나흥미롭게도이세포는체액성면역반응의초기관문(checkpoint)으로서아주중요한세포임에도불구하고,그기원및분화기전이다른효과기보조T(effectorTh)세포에비해비교적덜알려진편이다.특히대부분의연구가마우스모델에서수행되어사람에서는더욱이연구가미흡하다.이런맥락에서향후Tfh세포에대한연구가일종의블루오션급이라할수있고이를반영해서인지실제로최근에Tfh세포에대한논문이폭발적으로급증한추세이다.본종설에서는Tfh의분화기전,기능적특성,다른Th세포와의관계,전신자가면역질환에서의병적역할에대한최신

지견을소개하고자한다.본저자는이종설이자가면역질환을포함한체액성병증상태에대한면역학적발병기전을이해하는데일조를하기를희망한다.

본 론

1.체액성면역반응에서여포밖경로(extrafollicularpathway)

및여포경로(follicularpathway)

TD항원인단백질항원이적응면역계를작동시키는양상은그항원이외부유래인지또는자가물질인지에따라크게다르지않으

며,간략하면다음과같다(Fig.1).미감작(naïve)B,T세포는중추면

역기관인골수와흉선에서각각발생하여말초의면역repertoire를구성하게된다.정상인일지라도중추자가관용을회피해서발생

된자가반응적림프구를소수포함하고있는듯하다.말초림프조

직내에서보통B세포는주로구형의여포(follicle)를형성하고T세포는여포주변에산재하게분포하여B세포와는다른구획속에위치한다.항원성자극이가해진경우T세포영역에있는수지상세

포(dendriticcell,DC)에의해자극을받은naïveCD4+T세포는활성화되어각운명에따라효과기(effector)T세포로분화한다.이들중일부세포군은CCR7과P-selectinglycoproteinligand-1(PSGL1)발현이감소하고CXCR5발현이증가하여여포쪽으로이동이가능해진다.한편여포속에서도동일항원을제시하는특정B세포

가활성화되고CCR7발현이증가하여T세포구역으로이주한다.이두종류의세포는T-B사이구역(interface)에서만나상호작용하

여활성화되고그결과여포밖초점(extrafollicularfocus)을형성한

다[3].이속에서B세포는T세포에항원을제시하며,B세포는T세포의도움으로증식하고형질세포(plasmacell)로분화하여항체를생성한다.이런여포밖경로(extrafollicularpathway)에관여하는T세포를여포밖보조T(extrafollicularhelperT,Tefh)세포라부른

다.아직명확하게밝혀진바는아니지만이세포는나중에생기는Tfh세포의전단계세포라생각되어“초기Tfh”또는“pre-Tfh”세포라고도불린다.이과정에서생긴형질세포는클래스전환이나친화도성숙이미미한항체를분비하고약2-3일이내에죽는것으로알려져있다.이초기반응이후약4-7일사이에더강력한체액성면역반응

이여포안에서일어난다.여포밖초점내에서활성화된T세포와B세포중일부는CXCR5발현이더증가하여CCL19와CCL21농도기울기(gradient)를제공하는여포로이동할수있게된다.여포내에서이런T세포의도움으로B세포는재빨리증식하고활성화되

어조직학적으로염색성이흐린구형의구조체를형성하는데이를종자중심(germinalcenter)이라부른다.이렇게종자중심내에서동일항원을공유할수있는B세포의활성화를도와주는특이CD4+T세포가바로Tfh세포이다[1,2,4].Tfh도움으로종자중심B세포는체세포과돌연변이(somatichypermutation)및친화도성숙(affinitymaturation)과정을거치게되며또한IgG,IgA,IgE타입으로의Ig클래스전환이가능해진다.이런종자중심반응의결과로기억B세포와형질세포가발생하며이세포들은다시여포바깥부위즉,림프절의경우에는속질끈(medullarycord),비장의경우에는적색수질(redpulp)로이주한다.거기에서대부분의형질세

포는약2-3일내에죽지만일부는생존환경을제공하는골수로이동하고더성숙하여수개월-수십년간생존하는장수형질세포(long-livedplasmacell)가되어체액성면역반응이장기적으로지속케한

다[5].그러므로Tfh세포에의해유도되는종자중심반응은고친화

도의항체에의한만성적인면역반응이가능케하는필수적인요소라할수있다.

2.Tfh세포의정의및기능적특성

위에서언급한바대로림프조직내여포의종자중심에서종자

중심B세포의활성을도와주는특수한CD4+Th아형(subset)을Tfh세포라정의한다.이세포는CCR7loPSGL1loCXCR5hiICOS+

Hanyang Med Rev 2013;33:1-9 http://www.e-hmr.org 3

장은경 등 • 전신 자가면역질환에서 여포 보조 T세포의 위상 HMR

PD-1+의표현형을보이며상당량의IL-21을생성한다[3].이표현형

의일부는세포의이동성에,또다른일부는이세포고유의기능에관여하는것으로알려져있다.여포밖초점이건종자중심이건간에T,B세포의상호작용이있

기위해서는서로다른구역에자리한두세포간이동이있어야한다.이이동을좌우하는대표적인물질로CCR7과CXCR5을들수있다[6].CCR7은T세포영역에서분비되는케모카인인CCL19,CCL21에반응하므로,CCR7을발현하는세포는T세포구역으로이주할수있다.세포부착분자인PSGL1도CCR7과비슷한역할을한다.반면에CXCR5는여포로들어갈수있는티켓이라할수있는데,주로여포에서분비되는CXCL13농도기울기를따라가기때문이다.그러므로CXCR5hi표현형은T세포중Tfh세포에만국한

된특성이라할수있다.종자중심에서Tfh세포는어떻게B세포의활성화를도울수있

을까?B세포와시냅스를형성하고있는Tfh세포의표면에서발견

되는신호물질에서이에대한해답을일부찾을수있다.그런물질

에는CD40리간드(CD40L),ICOS,PD-1,OX40,BTLA,CD84와그어댑터인SLAM-associatedprotein(SAP)등이포함된다.이들중가장중추적인물질인CD40L은B세포의CD40에작용하여B세포의생존과증식을촉진한다[7].또한B세포의Ig클래스전환과체세포과돌연변이에필수적인효소인activation-induceddeami-nase(AID)발현을유도하여B세포의분화와성숙을촉진한다.B세포의ICOS리간드(ICOSL)에서Tfh세포로전달된ICOS신호는IL-21생성을촉진하고,IL-21는CD40L로자극된B세포의형질세

포로의분화를촉진한다[8].한편IL-21은Tfh세포의발생도촉진

하기때문에이시토카인은Tfh-B세포간상호작용을더증폭시키

는양성feedback역할을한다고볼수있다[9].CD84-SAP축은Tfh-B시냅스를안정화시키는데필요한것으로알려져있다[10].

3.Tfh세포의분화과정

자가적응면역이일어나도록유전적으로프로그램이되어있는동물모델에서Tfh세포가자연발생함을관찰할수있다.또는마우

Fig. 1. Pathways of TD autoantibody production. Autoreactive T and B cells develop in the thymus and bone marrow (BM) and populate in the peripheral lymphoid organs, such as spleen and lymph nodes (LN) (1). In these sites, autoantigen-pulsed dendritic cells license CD4+ T cells to differentiate to extrafollicular helper T (Tefh) cells, which in turn activate their cognate B cells to differentiate to antibody-secreting cells (2). In addition to this extra-follicular pathway, more intensive activation and maturation of B cells take place in the germinal center (GC) within the follicle (3). As a result of the GC reaction, affinity matured and isotype switched memory B cells and plasma cells plasma cells (PC) develop, and exit to extra-follicular area (4). Some plasma cells migrate to bone marrow in search of survival niche (5). Autoantibodies infiltrate to target tis-sues and trigger inflammatory cascades, finally leading to tissue damage (6).

BM

ThymusSpleen or LNFollicle

GC

Tissue

BM

B

B

GC B

CD4+ T

CD4+ T

1 1

DC

PC

PC

Long-lived PC

Tefh

Tfh

fDC

2

3 4

5

66



스를TD항원/보강제(adjuvant)로감작하거나lymphocyticcho-riomeningitisvirus(LCMV)와같은병원체로감염시켜항원특이

적Tfh세포의발생을유도할수있다.한편으로는invitro에서다른Th아형의분화를유도하듯여러조건을조성해주면invivoTfh유사세포가발생되기도한다.이런“Tfh분화조건”은필히Bcelllymphoma6(Bcl-6)의발현을유도하며다른Th아형의분화를억제해주는물질(anti-IL12,anti-IFN-γ,anti-IL-4,anti-TGF-β,IL-6와IL-21)을포함해야한다.하지만아직까지Tfh세포분화에중요한인자및그경로는극히일부만알려진상태이고아직많은부분

이베일에싸여져있는상태이다.특히Bcl-6가실제로필요충분한마스터인지에대한재고와invivo에서초기Bcl-6의발현을유도

하는물질에대한광범위한탐색이필요하다.지금까지잘알려진Tfh세포분자조절인자를소개하면다음과같다.

1) Bcl-6Bcl-6는zincfingermotif를포함하는전사억제자로원래는종

자중심B세포에서중요한분화조절자로먼저알려진물질이다

[11,12].그런데최근에세그룹에서동시에Bcl-6가Tfh세포분화에

도결정적인조절자임을보고하였다[13-15].즉,Bcl-6가결핍된마우스에서는Tfh세포의분화가억제되었고TD항체면역반응과종자중심반응이일어나지않았다.반면에Bcl-6를과발현시킨경우CXCR5,PD-1,ICOS와같은Tfh관련인자들의발현이증가하고Tfh세포로의분화가가속화되었다[13-15].이런결과는CD4+T세포가Tfh세포로분화되는데Bcl-6가필수적이고충분한“마스터

(master)”인자임을증명해준다.Bcl-6가어떻게Tfh세포분화를조절하는지에대해서는아직까지완전히밝혀져있지않으나,다음과같은기전이관여하리라가정된다.우선Bcl-6는CD4+T세포에서다른Th아형마스터전사인자의발현을억제하여다른Th세포로분화되는경로를차단한다.즉,Bcl-6는T-bet유전자에결합하여Th1세포로의분화를억제하며,GATA3발현을전사후단계에서억제하여Th2분화를억제한다[14-16].Bcl-6의Th17세포로의분화를통제하는기전은마우스와사람세포에서다른데,마우스에

서는Bcl-6가RORγt의발현은조절하지않고기능만억제하는반면,사람에서는Bcl-6가RORγt유전자의프로모터에결합하여RORγt발현을억제하는것으로보고되어있다[14,15,17].다른기전으로Bcl-6와Blimp1간의길항성이관여하기도한다.즉,Bcl-6는다른CD4+T세포아형에서높게발현되는Blimp1과서로길항

작용을하는것으로알려져있는데이는Bcl-6가Blimp1의발현을억제하여다른CD4+T세포로의분화를전반적으로억제할수있음을가설케한다[13,18].실제로Blimp1을항상발현하게만든CD4+T세포는다른아형으로의분화에는영향을미치지않았으

나Tfh세포로의분화를억제하였다.반대로Blimp1을결핍시킨경우LCMV감염시Tfh세포의발생이증가하였다[13].따라서Bcl-6

와Blimp1,이두유전자발현이어느쪽이우세해지느냐에따라CD4+T세포가Tfh세포로분화될지non-Tfh세포로분화될지운명이결정된다고할수있다.마지막으로Bcl-6가Tfh세포분화조절기능을가진microRNA발현을억제하는기전도관여하는듯하

다.실제로Bcl-6에의해발현이억제되는microRNAcluster를과발현시킨경우CXCR5발현이억제됨이보고[15]되어이런견해를뒷받침해준다.

2) IL-21과 IL-6Tfh세포의마스터인자인Bcl-6의발현을유도하는인자로는

IL-21과IL-6가알려져있다.IL-21은Tfh세포에서주로생성되어,Bcl-6가그렇듯이종자중심B세포와Tfh세포모두의분화와생존

에영향을미친다[19,20].수지상세포에서생성되는IL-6도역시naïveT세포에서Bcl-6의발현을유도할수있어Tfh세포로의분화

에관여할수있다.하지만이들시토카인이단독으로결핍된마우

스에서Tfh세포의발생이완전히억제되지는않으며심지어전혀영향을미치지못한다는보고도있다[10,21-23].반면에IL-21이결핍된마우스에IL-6중화항체를주사하여두가지시토카인을모두억제시킨후LCMV바이러스로감염시키면Bcl-6의발현이감소되고Tfh분화가억제되는결과를보였다[22].Invitro실험에서

도naïveCD4+T세포를T세포수용체(Tcellreceptor,TCR)자극

과함께IL-6를단독으로처리한경우Tfh표현형을가지는세포로분화가일어나지않았다.IL-21과IL-6는gp130/STAT3신호경로

를공유하므로[21]Tfh세포발달에있어서서로중복되는기능을할것으로생각된다.

3) ICOS

ICOS는CD28과유사하며TCR자극후발현이증가하여T세포활성화신호를전달하는공동자극분자로TD항체반응에서중요한역할을한다[24].ICOS또는ICOSL가결핍된마우스와항-ICOSL-항체를주사한마우스에서Tfh세포발생이억제됨이보고되어있다[21,25-27].Tfh세포발생에는ICOS를통한phosphatidylinosi-tol-3-kinase(PI3K)신호가중요한데,특히PI3K아형인p110δ가ICOS하위신호전달과IL-21생성에중요한역할을하는것으로보고되었다[28,29].ICOS발현의음성조절자인roquin유전자에돌연변이를일으킨sanroque마우스는ICOS발현이증가되고Tfh세

포와종자중심형성이과도하게증가하며그결과자가면역질환인전신홍반루푸스(systemiclupuserythematosus,이하루푸스라함)가일어난다[30].이는ICOS신호가Tfh세포발생에결정적임을단적으로제시하는좋은예이다.ICOSL가B세포이외에도수지상세포를비롯한다양한세포에서발현되기때문에[31],B세포이외에Tfh세포발생및유지에관여하는다른세포에대한연구가추가되

어야할것이다.



4) c-Maf

Tfh세포는다른T세포에비해c-Maf의발현이증가되어있는데,Tfh세포에서c-Maf는IL-21생성을유도하고IL-6와같이CXCR5발현을유도하는것으로알려져있다[25,32].c-Maf발현이결손된마우스는IL-21생성이감소하고그결과Tfh세포분화가감소된다.또한IL-21R이결핍된T세포는c-Maf발현이억제되는데,이는IL-21이양성feedback작용을통해c-Maf발현을유도한다는것을의미한다[33].c-Maf발현은IL-6에의해유도된다고알려져있다

[34].또한ICOS가결핍된T세포는자극후에도c-Maf발현이유도

되지않아Tfh세포에서c-Maf발현은ICOS신호에의존적인것으로보인다[8].

5) Batf

Batf는AP-1계열의전사인자로원래Th17세포와B세포활성에중요한것으로알려져있었는데,최근몇몇연구팀에의해Tfh세포

에서Batf의역할이매우중요하다는것이밝혀졌다[35-37].즉,Batf가결핍된마우스는invivo에서Tfh세포생성및종자중심형성이감소하였고이와같은결과는활성화된Batf가직접적으로Bcl-6와c-Maf유전자조절부위에결합하여이들의발현을유도하기때문

이었다[36].흥미로운점은Batf가결핍된T세포에Bcl-6와c-Maf를보충해줘도Batf결핍으로인한Tfh세포의감소를완전히극복하

지못했다[37].따라서Batf는Tfh세포분화체계의윗단계에서작용하며Bcl-6와c-Maf이외의다른Batf의표적이존재하리라짐작

된다.

6) SAP

SAP은SH2영역(domain)을가지며SLAM,CD84,Ly108과같은SLAM수용체의세포질꼬리에결합하여세포간부착에관여하

는세포내단백질이다[38,39].T세포에서SAP의결핍은수지상세포와의결합에는영향을주지않으나B세포와의안정적인결합에이상이생기고그결과invivo에서Tfh생성과종자중심형성이감소되는결과를보인다[38-40].SAP이결핍된pre-Tfh세포는여포

밖B세포활성화에지장이없으나종자중심으로들어가지못하였

다[39].따라서SAP을통한pre-Tfh세포와B세포간상호작용은pre-Tfh세포가발달되는초기과정에관여하기보다pre-Tfh가여포내로들어가서완전한Tfh세포로완성되고유지되는후기과정

에관여할것으로생각된다.다양한SLAM수용체중CD84,Ly108이Tfh세포에서증가되어있는것으로알려져있다[41].이중CD84가결핍된마우스는TI항원으로면역반응을유도했을때Tfh세포발달과종자중심형성및항체생성반응에있어서SAP결핍마우

스와비슷한결과를보여Tfh세포분화에서CD84의역할을시사

해주고있다[42].하지만CD84만결핍된경우SAP이결핍된마우

스보다상대적으로Tfh세포결핍이적기때문에,CD84이외의다

른SLAM수용체들이관여할것임을암시한다.

7) 여포 Treg (follicular Treg, Tfr)세포와 형질세포

지금까지우리는Tfh분화촉진인자를살펴보았다.그러나신기

하게도우리몸에는Tfh세포분화를억제하는기전도존재한다.대표적인예를Tfr세포에서찾아볼수있다[43].흉선에서유래된이세포는여포에분포하는Tfh세포의약10-15%를차지하며,Foxp3를포함한Treg표지와Bcl-6,CXCR5와같은Tfh세포표지를동시

에발현한다.중요하게도이세포는통상적Tfh세포와B세포의작용을억제하는기능을갖고있어,체액성면역계의항성성을유지

하는주요요소로간주된다.또한다른보고에서형질세포도Tfh세포의발생을제한하는음성feedback작용을한다고알려졌다

[44].즉,체액성면역반응의최종산물인형질세포는naïveCD4+T세포에항원제시세포로작용하여Tfh세포로의분화를억제한다.실제로형질세포가결핍된마우스에서Tfh세포수가증가함도보여이런가능성에힘을실어주고있다.

4.Tfh세포와다른Th세포아형과의관계

Tfh세포를포함한모든Th세포아형들은모두naïveCD4+T세포로부터기원한다.즉,naïveCD4+T세포는항원성자극을받으면Th효과기세포로분화하는데,이때항원신호의성격,주변시토카

인의종류에따라각기다른특성과기능을가진아형이발생하여서로다른면역반응을매개한다.Th세포아형의분류는1986년Coffman박사등이Th세포군을제1형(Th1)과제2형(Th2)으로나누면서처음시작되었다[45].하지만그이후더많은아형이있음

이알려져서현재는Th세포아형을Th1,Th2,Th17,regulatoryT(Treg),Tfh세포로나누는추세이다(Fig.2).

Th1세포는IL-12,IFN-γ가풍부한환경속에서naïveCD4+T세포가자극될때잘발생하여세포내세균에대한면역과자가면역

성을유발하는반면,Th2세포는IL-4에의해발생이유도되며세포

밖요인에대한방어및알레르기와밀접한관련이있다.Th17세포

는TGF-β가친염증시토카인인IL-6나IL-1,IL-21등과공존할때잘발생되며말초조직에세균이나곰팡이에대한염증상태와자가면역질환을매개하는주범으로간주된다[46].Treg은흉선에서고유계통으로자연발생되기도하지만말초에서다른아형처럼na-ïveCD4+T세포에서분화하기도하므로Th아형에속한다고할수있다.그렇다면Tfh세포는기존에잘알려진다른Th세포와기원및

기능적인면에서어떤관계에있을까?이들은모두공통적으로모두naïveCD4+T세포에서항원성자극에의해발생이유도되고,각아형특이적마스터전사인자의통제를받는다.“마스터”라는표현은어떤특정세포군이발생될때필요하고도충분한인자를말하는것으로,Th1,Th2,Th17,Treg아형에각각T-bet,GATA-3,



RORγt,Foxp3가있는것처럼,Tfh아형에는Bcl-6가있다(Fig.2)[13-15].Tfh세포가다른통상적인Th세포와다른점은여러가지가있는데,우선작용하는장소와기능이다르다.림프조직에서분화된통상적Th세포는그림프조직을떠나감염이나염증반응이있는말초조직으로이주하여그곳에서세포성면역반응이나,알레

르기반응,또는염증반응을매개하는반면,Tfh세포는그림프조

직의여포로이동하여B세포에도움을제공한다.둘째로,통상적Th세포는주로각자생성하는시토카인을통해효과를보이는세포임에비해,Tfh세포의주된기능은시토카인분비라보기어렵

다.물론Tfh세포도IFN-γ,IL-4,IL-17을분비하지만그생성량이통상Th세포에비해현저히낮다.하지만우리는Tfh세포에서비록소량이긴하지만Th1,Th2,

Th17아형의대표시토카인인IFN-γ,IL-4,IL-17을생성함[25]에주목할필요가있다.이는Tfh세포의기원을추적하는데중요한단서가될수있기때문이다.Tfh세포가Th17세포와여러면에서유사점이많음도유용한정보가될수있다.예를들면,두세포군모두IL-21을생성하며,분화에필요한물질로c-Maf,IRF4,STAT3등을공유하고,B세포활성화를직접도울수있다[8].그렇다면Tfh세포는다른통상적인Th세포와기원이다른독립적인계통인

가,아니면T세포영역속에서분화한Th세포가여포로이동하고더분화되어Tfh세포가되는것인가?이는오래전부터논쟁거리였

는데,Tfh세포의마스터전사인자인Bcl-6가다른Th세포의발생

을억제함과,invitro와invivo모두에서통상적Th세포의발생이

억제되는조건에서Tfh세포의발생이더촉진됨이밝혀지면서Tfh세포가그들과다른경로로발생되는하나의독립적인계통으로인정되었다[14].하지만보다최근의다른논문들에서LCMV에감염되었을때Th1세포로부터Tfh세포가분화하거나,장내기생충등에감염되었을때Th2세포로부터Tfh세포가분화함이보고되

어,Tfh세포는독립된계통이기보다는통상적Th세포가더분화및성숙된최종단계로보는견해도있다[3,47,48].하지만이런보고가고유Tfh세포의존재를부정하는것은아니다.아직까지는Tfh세포가Th17에서유래한다는보고는없지만Th17세포와Tfh세포는여러면에서유사점이많음을감안한다면,Th17세포가Tfh세포로분화될가능성도많아보인다.심지어는Treg세포가B세포

와CD40가제공되면쉽게Tfh세포로전환됨이보고된바있다

[49].이현상은소장의파이어반(Peyer’spatch,PP)에만국한된현상이었는데,아마도다른장기보다는장내세균총에의해만성적면역반응상태에있는장연관림프조직(gut-associatedlymphoidtissue,GALT)에서는Tfh세포로의전환이좀더용이한것같다.이와일맥상통하게LCMV에의한만성적감염상태에서는Th1세포보다는Tfh세포가,급성적감염상태에서는Tfh세포보다는Th1세포가더잘발생된다고알려졌다[47].그러므로종자중심에서발견되는Tfh세포중에는오로지고유의프로그램대로발생한고유Tfh세포도있고,다른Th아형로부터유래한Tfh세포도섞여있을가능성이크다.하지만전자와후자가표현형이나기능적인면에서동일한지다른지에대해서는아직미지수이다.또한최종분화된Tfh세포가얼마나오래생존하며얼마나안정적인지,또한다른아형으로다시전환될수있는지에대해서도더연구해야할것이다.

5.자가면역질환에서Tfh세포에대한연구현황

Tfh세포분화의부적절한조절이전신자가면역질환을초래한

다는것은많은동물모델에서익히잘알려져있다.여러모델중Tfh세포의발병에의역할이가장선명히드러난모델은아마도sanroque마우스일것이다.이마우스는자가항핵항체와자가항-dsDNA항체가면역복합체를형성하여사구체신염을유발하

는등여러면에서사람의루푸스와유사하다[30].이마우스는앞에서설명한것처럼ICOS과다발현으로인해Tfh세포가비정상적

으로과다발생하므로,Tfh세포발생과루푸스발병은상관성이커보인다.그러나보다최근에roquin유전자가아예제거된마우스

에서ICOS의발현이증가되긴하지만루푸스소견을보이지않았

기때문에[50],Tfh세포만이루푸스발병을책임지고있는것은아닌것같다.이외에도다른Tfh세포분화에중요한인자가결핍또는억제된모델을활용하여Tfh세포가질환발병에관여함을보인경우도많다.예를들면우리연구실을포함하여여러그룹에서IL-21R결핍마우스에서Tfh세포발생과자가면역질환이동반감소함을보였다[9].CD40L또는ICOS신호차단제를투여하면Tfh세포

Fig. 2. Development and plasticity of Th subsets. Naïve CD4+ T cells differentiate to distinct subsets of effector cells upon priming with antigens. The cytokine milieu during priming is important for selec-tive expression of lineage-specific master transcription factors. Each subset is prone to be converted to others under certain conditions. Th17 conversion to Tfh is speculative to date, so indicated as a bro-ken line.

Naïve CD4+ T

IL-12, IFNγ

IL-4

Th1

Th2

IL-4

Th17

IL-6, IL-21

Treg

Tfh

LCMV

Helminth

?

B/CD40(Peyer’s patch)

IL-6 (IL-21), TGFβ

IL-2, TGFβIL-21, IL-6



와종자중심의발달이저하되고질환이조절됨도Tfh세포의역할

을보여줄뿐만아니라치료표적을제시하고있는점에서중요한의의를가진다[47].사람에서는림프조직에서직접Tfh세포를조사하기어려운점

이있으나,대신환자의혈액에분포하는Ig클래스전환된CD38hi형질세포가종자중심반응을입증하는중요한단초로활용된다.실제로질환활성도가높은루푸스환자에서이세포의수가증가되어있다[51].또한최근에혈액속에서Tfh세포와유사한표현형

(CXCR5+ICOShiPD-1hi)을가진세포를동정하여순환Tfh(circu-latingTfh,cTfh)세포라명명하였는데[52],이는Tfh세포의전구세

포로생각된다.중요하게도cTfh세포수는루푸스,쇼그렌증후군,류마티스관절염,소아피부근육염(juveniledermatomyositis)과같은자가면역질환환자에서증가되어있어,이세포가여포에있는Tfh세포와상관성이커보인다[53,54].또한가지주목할현상은림프조직이아닌환자의병소(예를들면루푸스환자의콩팥과류마

티스관절염환자의활막)에서딴곳종자중심(ectopicgerminalcen-ter)이관찰되기도한다는점이다[55,56].이런조직은말초병소에

서필요한대량의자가항체에대한수요를국지적으로해결하는전략이라생각되며,여기에서도Tfh세포가필수적인역할을할것임은의심의여지가없다.

결 론

Tfh세포학은21세기에새로이정립된학문이다.지난십여년동안의연구는Tfh세포를하나의독립적계통으로자리매김했으며,아울러다른아형과의유기적연관성도제시하였다.Tfh세포란정의상여포속에분포하는Th세포무리를통칭하는용어이기때문

에,분포와기능에필요한공통의속성을공유하면서도시토카인분비능이나활성화정도가다양한여러세포군이섞여있게마련

이다.실제로최근에종자중심에Tfr이외에도invariantnaturalkillerT(iNKT)세포가분포함은Tfh세포라불리는세포들의정체

가다양함을대변해준다.Tfh세포는TD항체반응에결정적으로필요한관문의역할을

한다.우리는이종설에서자가항체생성에관여하는자가반응적Tfh세포의발생과작용기전및자가면역질환에서의Tfh세포의niche에초점을맞춰기술하였다.하지만Tfh세포의병적위상은자가면역에만국한된것이아니고알레르기및장기이식거부반응에

서도유사하게적용될수있다.반면미생물에대한항체는우리몸을감염으로부터보호하는역할을하기때문에그런경우Tfh세포

는우리몸에이로운역할을한다.그러므로감염이나면역결핍상황에서는Tfh세포의발생및분화를촉진하는방향으로,반대로자가면역질환,알레르기,장기이식시에는Tfh세포의발생을억제하

는방향으로의면역조절이필요하다.이런맥락에서Tfh세포의분

화경로및작용기전을선명하게규명하고이를바탕으로Tfh세포

의발생및기능을선택적으로촉진하거나억제하는기술의개발은상기한바와같은면역질환을극복하는데큰도움이될전망이다.

ACKNOWLEDGEMENTS

ThisworkwassupportedbyaNationalResearchFoundationgrantfundedbytheKoreanGovernment(MEST;2009-0081790).

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