I'

I

i

¡nnuio¿.|¡.t.ñr R.et¿* t'¡)l). !in. l. f'p l_lóR.r'nnt ¡i¡'l¡bl.dircrly frdm lhe públúh.rPhó(*of'tng fE.nútcrJ hy lic.nsc dnly

CONGENITAL T-CELL RECEPTORIMMUNODEFICIENCIES IN MAN

BALtsINO ALARCON*. COX TERHORST

L(boralort- of Molea ar Inunuttology, Dana-Fsrber Cunccr lttslituIe. HarwrdMetliul S¿'hool. Boston. MA 02115, USA

ANTONIO ARNAZ.VILLENA, PAI.CIMAPEREZACIEGOANd JOSE RAMON REGUEIRO

lnmunologia, Hospital l2 de Ocnúre,28041 Madrid, Spain

Thc T-ccll receprcr {'I ('R) for antiEcn is a complcx consist¡ng of at least sevcn polypeptides chains"Iiochains lirrm th; ck)n(,typ¡c heterülimer. which delcrm¡nes onligen-specificity. Thc other llve constilute

ihc mr,non..rrphic ( l)j c,tmp,tnenrs. r¡tich irc thought kr he in''olvcd in \ign,.lrrxnsdu.titnr. wc hirve

r..oorlcd ¡l lu;ilialdctccr in túe liurf¡cÉ e¡prcssúrn ofthc'l CR/CDi complexon olherwisc phcnolypicall,

n<irmal -l lymphocvtcs. As a consequence of the surface defect. an impaired Tlymphocytc ¡lclrlall()n-

r'frt,t"*¡t t¡i tCR and CD-l compiex by tx)lh anliSens dnd mik)gens ¡s obscrved in this tyPe of

inrnru'n,dcfici"'ncy ID) for which wc prirpose lhe name ICR lD ln contr¡st. norm¡l pr.liferatiYe

,"ro.,nr"* *"r" ,ó.,rr,ler! to TCR_indcpindent ¡clivation or proliferalion sign¿ls li'e: antiCD: phorbol

.iiJr.s a¡<l IL-li_ We believe lho¡ dñer lD wilh similar clinical and immunok)gic¡l character¡sl¡cs.

,lescrihed before the gencr¡l availabilitr- {rf monoclonal anlihodies. may have also been TCR lD Setcre

anJr¡ild ctinicat ptrer'r.r¡-pcs of the diseast'cris¡ shich corrclate wilh diff€renccs in thd lc\.'ls lrf TCR

s'rface expression an¡l of'f-cell functi()n i¡ !it¡o, The biochemical basis of the defecl in t)nc ol the ciNes

i¡"ii"t.il¿¡"¿ is an ¡mprired association of CD3-( chain wilh lhe olhcr cha¡ns of lhe comPlcx This

Jeie..r prcncnre,t rhe tn¡t;ra¡i()n ¡nd tr¡nsp()rt of the incomplele complci( t() the ccll \urh(c. Dut tt) thc

"i"f,i-.!¡".1, narure t¡f rhe TCFJ,CDI c(;mplex it is possible thal other biochemical delccts ií ICR

assembly may also Sive rise IoTCR lD.- if,. ú.,,.ripti,tn .tf mitd as well as a severe phenotyPe in TCR ID p()i s ¡r ¡ lhrc\h( d effect of TCR/

CDil exprcssiirn necess¡rv f()r nr)rm¡l T cell functi()n ir¡ r'¡r) since mild'tCR lf) is clinicall¡ as\ mpk)mrtic

¡n,..onli¡st. severe TCR lD beh¡ves as ¡ clinical SCtD. wilh clear autoimmunc leatures ¡nd p()[ound

l!mphoid l¡ssue dePlctr()n.TCR ID and otñcr nrlurxlt! occurrrng SCtD variants may shed light on fund¡mcnlal qüesti()ns of lhe

dclekrpmcnt. tuncli()n and b¡()chcrnislr! of lh(' i¡ r'¡n immunr'sl-slcm. Thtif sltrdv rlnd chtrr¡clcfrralxin

i1.,., "ó"nr ,¡" door lo somatic gene tlerapy in this kind of disorder' which is ¡n obvious goul in lD

research.

KtY WORDS: |-cell rl'jccpl,)r. lmmunrxlctreiencr. ( D.f i

INTRODUCTION

Primarv immunodcficicncy {lDl st¿tcs are cl¿ssically rccognizcd on thc basis ofclinicaí critcriar. namely the presence of m()re or less severe. but repeated'

bacterial. funsal and virat infeitions. The availability'of analytical mcans fbr the

cha¡acterizatión of these disorders led to their classification as predominantly

humoral and c€llular ID, and fu her sophistication ()f laboratory methods has

allor ed the krcalizalion of many ID abnoimalities within th!' intñcate \^eb of the

O lee{) H¡ñü¡ Ac¡d.wc P!hkh.r\'GnhHPnnted ¡¡ü. UorNl l(i¡8¡oñ

"1) \.r"i ..

"¡ r) \^hom c()rrespondcncc sh(,uld ht ¡dilr,iJscd

2 B. AIARCON AND C. TERHORST

illiillli;,,i."T;[:'1,.H:i:..'.];i i" 1l:l! become. apparcnr thar some. hearthv

¡gpJ; ;;- ;,;;';;:¿ii,is,,l, ;ril'fili, :':Jl.,,''fr,iliff:1fiil .:H,,Tli

l,:;iii:ff3':l¿i[.i"::]iü:l:Tll?,,L..,,i.,'.',,.,j3i,|.ilJ,T,ü*lff,l]ii"t:,iT,il:

ll{i'ül;:yü,i,tltü:'i:lti'" ::t[,1't"":in il¿:'s:"xtffiiilü til,i,,"ilT|f.1"::ff$"}'"';iÍi:itjllJlitliTL"l. .i'."r"ting i: ,,"i"üli.'r n,".r,",.,. i,,r,¡.1i,

ii;¡::ril,ffi l¡¿!-, bi*ll."1ffi*:,,;;:ffihcrlrhv individuals lmild phcnrbeenpreviousryrecognizebr"l','rlJl(:::;!ijl[.",.* jfligl.$"*,fi liili;with normalT- and B]cell nuníbers.

The T:.Cell Re<.eptor

Il:,:::..1:,r ft,t anrigcn of human,T _cells.*. composctl ot.r\4o gtycoprorc¡n\ w¡rh

üi'i"':,filtil. ,:?5'1i.

";.Ti*xjl jiilliüi;_.,,J1j"j: ; tiii liui;, :l:polymorphic and share cb.mon structu¡al Teaiuies'- wir^h .rmmunoglobulins,

iiFi:ll'¡ffiT i:T:til iit f ;ffi."*ffi li¿',

"..1'1I.,?Jf:[x,irff

j,?*?üand diversity (D) scquences.

iffñiH,r,1J:it'.+i*:il'iiJ.{t::il,.,"..jü1;r.i,,T¿},IT.i,.f,fi :rxr,:

trfl,í"i*",fi t+i':*iii:i¿.ffi ii[il:i*tiiit:;lll;iil'ltlñ[Orig:t",.

class r or class lt proéins "r

mE-rnl¡_ n¡riá.oipatiUttiry compt.*

,.."111T {.,T.:l4type are responsibte for-¿nrigen recognition by hetper T ce[s as

ff[nfl #? +::.il :ii';; J]'. ":i:

^'l -T ::Io "p'"-'J n!.' v7á.

"óep to r is s ti I r

3 9!1-49 r:ie, r'eIüü ff; J' i: ii'.ff3 :T iT"",t"jii,H' p roducts' : andprotein derivative, (PPD) oi Mycobocterium leprae and r. ,rr;r.rr#ll, Íi ,?iJtÍii

lli:i"::iH/Ji.1"xju[","ff:¡q1**:.*""'4i:;ik:*:ili#;specifically recognizes iDl,^. Hoo,euer. rhe exrenr oi'üiii,rlr*"u.n among all,,;:,ííL"J$.;l:ngTrelrs. as *el as rhe diverilit J;;;;"; ,il, rhcy recosnize.

The CD3 Conplex

I9R,:/p as.well as TCR-y/ó receprors are not exprcs:rcd alor

ü[f['TllüT'.:i;::Uil $',?:tT1':ig;.;::i:*k;::{:? t:l?.3*l;

1--('Et-L Rt]('EPfoR IMMUNoDEFI('IEN('Y

The TCR/CD3 complex

CD3 ProtelnsFigurc I Schcmat¡c rcprescnlal¡()n of ¡he TCR CDi coñplcr on thc T_ccll m¿mbrirnc' dra\¡n

.,pirr,^imurct¡- ¡r rc¡lc. i in¡ic:Lrcs \ilcs rh¡l are phosph()rvlat.d ulorr crtitirtr)n: _SS- indic:ller the

cri.rcncc,'f tii'ultid,: liri(llr\: ¡nd lhc hr:rnchr\ indicxlc N-tinked glvcr)s\l¡li() l hc \loichiomclrl ')flh'rdifl¡rcnt ruhunit\ ¡\ lxrgcly unkno\"_n

Tr¡t¡ of the CD-i polypeptitle chains are glycosylated' CD-j-y anr.l CD-3-ó; and the()ther t,,\(). CD-j-i a¡id CD3-i. are not. CD3-6 forms homodimers and. at least in

nrurine T cells. a small petcéntage ot CDJ-q'is di'ulfidc-linketl to a 2lkd non-

clrcosvlatcd pr()lein. C D-1-4r-. All these proteins are expressed l(lttcthcr $ith thc

?Ón.ír t¡e ecll surt¿cc and urc believcd i) participatc in the signalling resulting in

T-cell activation.

Complete TCR/CD3 Complexes Are Required for Expression on the Cell

Mentbrane

Durine T-cell development there is an orderly expression of CD3 and TCR genes

CD3 g"ene. arc expre..sed from vcry early stages. prohahlv during lhc prcthvm()cytc

stace.'since human fetal liver c()ntains cells \^'¡th intrucelluli.rr cD3 chains at a time

,, ;l ;,,11,.:

i*:; '

x.i. .r;t:

, AT-ARCON AND C, TERHORST

hefore lhese arc firund in the thvmus¡N. .The TCR genes tre re¿rrransed ancl

Tp:_.,:::d .:qu"1!1tly during matuiation. Th" firr s.di;;':ó, rorowed by rcri-y

""¿'rcn-¡.'i'r,. Tcn-r" rii"*Iil:,ijli8;.llffS[i:':t1'ü¡ii1,lJ1"É{,ü.8ü!;';]1ft.J,,#l.T,iííi-,.;.J;:Hl;ilffii*ltwo separate lineagesr. Alth<iugh im.marure rhymocy,"i,,.,i"ilii. cyt()ptasmrc CD3r.nalns, tl ¡s only after the T(rtrvmocyte. ai,pái;;; i'ó:3 ü,T;I.:,i: lÍT:;ff*ins arc cxprcsscrr rhanhc

,rl,fJ;frffi:iH.'iil,J.1_:9',, mutanrs rhar tacked the abitirv- kr synrhesize one**p,,.,...r nn-ih.-';;ri';;;:"ii"t:1."J,.Tü

",?q,l11liÍ":3: ;ll.ii:ifl. i:i11c1s grPcssion of a cDi charns bur ,,ili'.,ri"t"i ."y,.,pl"riii rcn_,lnd TCR_

Í,,:i!i^ir;id;i$t'.ii J

n.";:l,:il, Tiil;:j;,'#*ii j::;:t,i,:: iilmcmhrane. This retention svswhere a.ssembry .i,r,.Tériiufi fffr.,J_'',Tf:lrriL:$,lHllmr_.".:i::i"jlsrcps. whcrc CD3-y, CD3-ó

""¡ cój-Ii"?r? ¡.lili*r.,l'*n¡ch rcR_a anjrr'K-É arc adtled. Finallv CD

31"_._1;,.,¡ 1"*i ilá, ii.íí, r,ll,,:liT

ff Tili^rl" u"JlI*r*fi

":i* I, f ;expressron of rhe TCIVCDJ i^.Tp]* T:,hqr; i".'.r i'¡'..."ir.,ors is CD3_cu.LuJ-ü, rs believed ro parriciDate in'assemUly. o.t ttre iCn-ó'ói

"o.pre*, since ir isiil::fi::!1# in the ceil wrrtr rncompreiJbui ;;, *i h ;í;;*mbretr rorms or

nlJff,í.:.r"*:1,;l':..1:ll :l"ifno,.te com.ptexes is not tuily efricient. since some

express the orhers, utu"it "t "

u"$illJt] cells thal lack somi or *re .uuunitrlt¡¡i

Actiwtion of T Cells via the TCR/CD3 ComplexThl'¡imularion of T ce s with ligancls of the TCR_CD3 complcx.illPdi* uno. rirne"nic'i.ii¡nr^r..uro in a series;;;;;;;: ,'n"".,n,ilJ"li*il)expressron of rhe Il-2 receptor 1CD25) anO ,¡,¡rri.lv i" or"iii.,pheno'n.nu,'"iurrini rii,'r"iñi

3!.rrvar19n of- the rciVcb3 "..Ti:l';"t¿":?lncrease in the concentration of intracellular f*. á;il""d il phosphorylation:l^T:li,l¡ amons them CD3_y. and p-,.i" li""ü'C',"rütr

ff flf Biü;{:: ::nxi. l,,llr#.,,*'i,t#:ti'dXli}ildilq:l,it:a"clrvates phospholipase C tpLC7._rr-\ ts a membrane-bound enzvrlnc hydrr)lVsis of phosohaticlroacyrs,yceio,DÁ",:ü:i;&:i;,;lHl,.di.il^:ii.1[',Hll,fii:1fjl]i,iland exlrace ular sroresr-. DAG aa¡?res,pxC. *ir-ü ui"a"'iii,iJ,.y,"r.trc sidc oftie plasma membrane and Dh()sphorv,lates a scricr ,,t fr,ri.'in, al scr¡ne orrnreonme residues:.. lt ¡s beli¿ved- thar..borh-lhe *. i"

.i",i"iir¡"¡"r calcium andactlvation of pKC result in the ac-fvation,of the T cell. because the addition ofcalclum ionoph('res and PKC aclivat<n such as csler\ r)f ph()rbol acti\alc T cclls loprotrtera¡e. Also. G proreins r...

1:-g. impticared t..uui. ,lurinlu* uoritle andanak)gs of GTp. which are direct acttva¡o¡r of G prrrtcins. :rre ahlc to sltmul lc Tlil ,i'riillil:,*"r" However' n¡¡ link has v.r u".i ti,unJ i,"i"*"'rcn acrivari.n

-Í..CELL RE( EPI'OR IMMUNODEFICIENCY 5

T-cell aclivation through the TCR/CD3 complcx results lso in the

.,h,.,.nh.,r1l¿ti,,n ot CD-1-! üy I tyrosine kin¿st'"t'r' The possibilit¡'thlt this kinasc

i..";'il;i:i' ';ilich 'i. -,"',r.loi.,'i íittt cu'r ¿nd CD8. is ccnainlv appealing' "'ii.r'o.u".. it ii still unknown whar kind ol signals result fr6m the phosphorylation ()[

Cil).i-7 in Ser resitlues antt o[ CD-j- i in Tyr resitlues (Figure I 1'

CLINICAL MANIFESTATIONS OF CD3 DEFICIENCY

We havc rcpor(cd the cxi!'tcncc of a severe (V)and a mild (D1 phenotype of CD'3

deficiencv in a sinete family that we have studied.-'i-h.'"Ló,"ir".'(V)had some of the classical SCID features (Table l): failure to

,hri;;', i;;á;i;ü; '¿¡átttroea and fatal pneumonia' The parient.had no historv of

:,h";;1" ItAñ or tungal infections, eczema' or cbronic moniliasis' No

T.blc I Summary of clinicaland immunological ñndings in presumed (P)and confirmed (C)severe

TCR lD Dali€nts.

Slatus P

Sex MaleA8e of decease (monlhs)10

Causcofdecease PneumonúFamily his¡ory of lD

Castro_inteslinal featuresweigh loss NRDi¡rrhoea +Villus atroPhy NR

PPPPMale Mab Femále Male

30E410pncumonitis CVHD \ePlicremr¡ septicc('mlJNR' + +

cMale

pneumon¡u

+-+-NRNRNR+

42 41 44

NRNR+43

NR

+++

+

Normal

Depleled

NRNR

NRNR

Depleled

Reference

Au¡()immune fealuresB lymphocytesNumberFunctio¡

T lymPhocYtesN!mberFunction

Lymph()id tissue

40

NR

NormalLow

Normal

D€plelcd

Normal Norft¡lLow L.oe

Normal NormalLo\r Lo*

Norma¡

Normal

Depleled

N()rmalLow/Normai

Depleted

,NR - ror r!co¡d.d.

dvsmomhic features or bony abnormalities wefe detected. Slool cultures grew

ir"h";r:;'ii; ,';;;;;dtt án¿ urá"¿ cultures grew Yersinis enterorcl ica Respiratorv

;;;r;ii";;-;;J pulmonary biopsies gre"w untypable- (beta-lactamase positive)

ñá"-iilñ¡u iri""*o". Á gu Úiopsv ár 18 moñihs of age showed a flat mucosa

B. AI-ARCON AND C. IERHORS'I'

l;ll"j"Il',Pfiili;il.nl.,;,',',1.1'"""' \\ith ccliitc discase " serunr auroanrih('(tie\suggc.sting "; ,;a;,i;.;;;:".i,J,""01'ñ,:iiurt"J,,:i,,,'1. Xl,r::|.;*" ;Xi,;lyntph<ryrc counts (28-j5 p¡c.,niprcmcnr c.r r,,:,g),ir,"u,i.rtlj lir.ü.'.il.1;l',1,:;1ll:Iil:,:J,,iilll,;:l*

ifü, d'üü:r,l,,, ill'ri^l;l'.: "i? -"J^**, i ; il:i,;i"i¿

( c n,e r. pa, h v, a n d

iiü?',:'j;"Ili;iti-*:;:..1*.::iÉ,s+x.,,,,_ff jfi [ili#.'Hfi#[{!iiij,,l!:ü',"^.iil llJ:il',s."Iliiig,',t, ]lx5#.'*1ff g::l*,lmjli]il''.,iilllT,i',il" illJ,[Tl{iü"1:i'",-:il.{i[:*il;,H,',|j;,,.r,.,f :,]HXlio.5 cm rhick. 1.2 cm wide). ThymiccpirhetruÁ ;;;;;;.:;,;r,irmphoi<t etements

liii.i-¡'.'':',,ü i,ii'i':'."1;"Í,li'uxl,'nili'*:Hujli i:ijll;;¡l';i:fff?iil:1i:*: t#:i{,Tii,lÉj :'L Í;'f t;,i";i:i:x il"tl.;:},,iftl n.::n* r**i8Éffi ,:xr"s,'*itfi 'fi!;:üiTIiTif *li;i:l.1.:lHii*fl .,,tq

[r:!rJ".rü:l'"i#:rü:."?:,t]i":tii:ilit*:*"lins:iJtlTilj,Tjff :"ifl [',:'.',H,1[:l;rxif :'":::lllt,ilil*irux,**:jx:xT,f,:parents were insrructed to keeo in-close conio.t _tt tt.-ñofriiail *nn cough. feverand respirarory disrress. Durins tr,.¡" Iurt uJÁi.i¡onl;;;ú.il:ñL,n'.nr resutted in

:: jlilitJ ¡.o"Ti'¡l',!g'#'.íf 'ilX;Hi:1..,?,J:t[il:,:",ilrff il:il:li:'.',".1ra g,Ti,T,'.,"#xlil¡i-::tti,i":i'#I.#*

i*ü'#xl""il,.#i:":X.,,iii,lJi,:i,'.:'":'Xi';f; fi il!':ff ;#l131;.ff q-ij1#*"i?+..':Ht

iüi:j:jil.ill J,Tr'ffi :fi.,,;'"::.i jlll;i¡ *ll;"¿iilllitu[l{ ii*ipropositus. This discrepancv co,

óbsarved q,i""i¡,iii"i'[frif#.]:"'.r.¿H. ,&fi:1,.,,,:"i.f;:F:"]?, li"t.:i

.;,i:;drrterences.hclween (he rwo children: {j ,rf,. j-fif.á,i". .irinir.s ot mil<l TCR

i[] jir.vi'iriil.jd;1ifi T,:}fl?iiF:riiul$r.::,**i*:i":tsrncc sih D has 3-.1 times hicher num.bers .f fóñr;i lyrnpf,i.vl.. ,t un sih V r.ls¡tr D has higher IgA tevets ihan sib^V r.{., s¡u üias ;";;;";;ür, of pcriphcral1,9"d- 9P8 r tymphocyres (mean l2y.) tr,- ,iu ürn".an' jó:ijlirl

sib D has no

:üipTir rf :i.fiil:t',:lillli'i¡,i¡ [",",9 i JJ'#* J{*i: rcq u i red ro r

ig:iüi¡rj{ir**J*["¿i¡\f.g$f .f ,tri.fi ¿LT.iiT,.-*irarses qucsrrons about rhe tr*,*,"r, ,,r-tn.tiañ li, -iiii,

rr^,"nc response roInleclton. and suggest\ that othclrne mlrd dcrect in ca.r"in.i..rn'r,url"-jrt_ll

aclrvalr()n palhways may compensare frrr

.t :', :':',

CHARACTERIZATION OF TCR II-)

Phenon'pi<' .4ntL"sis

The most Drominent feature in the two cases of TCR ID studied is the defectiveexpression' of TCR-associated structures on the surface of peripheral ,Tlvmphocytes (Figure I r. Mon<rlonal antibtldies recognizing most TCR-¿/É{wi¡ r. 'gt''f etl-¡i ) and TCR-y/ó (Tiy A' TCR delta I ) heterodim€rs' or the

monomorphic CD3 componeni (OKT3, Leu4' T3'..), consistently showed around

l0-fold kiwer levels of'TCR expression on peripheral blood and cultured Tlvmohocvtes, as compared to normal controls". Cells that were posilive for the

ÍCVCó-¡ complex invariahly showed a lower fluorescence intensity per c€ll thanditl the control lymphocytes: álso,3-4 times fewer such TCRr"" cells were observed

uoon serial anaiysis in the individual with the more severe form of TCR ID as

cómpared to the intlividual üth the milder phenotype (see below).-In contrast, normal percentages and expression levels were observed for CD2,

CD4 and CDg (the t*b luttet in a mutuaily exclusive fashion' Figure 2)' and-this

indicates that the majority of the lymphocvtes lacking normal levels of surface TCR

Tly/6

T.CELL RECEI'I'OR IMMUNOI)ETICIEN('Y

rLa/ F

l.

8

Fi¡¡re2Phcnolrp€ofpcripherulbkxdlymphocylesinTCRlDlndirectimmunonuorcsccnce\¡asoe-rf.rrmcd t ith aniih"diei \pccrfic for lhc T-cell markers indicatcd in lhc figurc The \trticrl bt¡r in e¡ch

i"n.f in¡i."r". rhc upp,rr limrr ,tl rh( n(gali\c control \l¡ini¡rg'NEC . Simil¡r rt\ulh $crc oblitincd iD

i',rh l( R ll) \rbhnlls qrlh rll lhe !rnlr-(DllrndJnlr-l( R rnlth'di'i\ u'(d '

ü &.rL L

13 6. ATARCON AND C, TERHORST

were *mature" disjunctivc CD¡l or CDg cells- It is wo¡th noting tha one of the twostudicd individuals {D). who is orese¡tly tr_ealrhy. *"ri.i"ffi'ñ"á a low ro normalnumber.of CD8.T ce's, w¡t¡'a co¿7cód;áir" ii'i.s."i# retevance of rhisobscrvation remains unclear (see below).All other tested leukocvte surf¿ce^ mole_cules were normally expressed (includingcDt rb. cDl4. cDró. cós7. cDt8. cozo,óoii. ür.;ii,_r¡]_tt-on...p,

Fu nc t io na I Abno rma lit ies

As a result of the low level of TCR cell_surface expression. T_ceJl proliferation via'-t..,,JÍ.l"i3llffi:ilT:',í::t 'Ttlred

in these cises or rcn ió, as shown bv rn

illlb:¡;í;e.r1i#.*.itt¿#?';",i,li;*?.'.J:r1""'j','ü,i*g:lin.".:lo _i.:gyt of T-celt tuncrion essenria y 'c_onfirmeá" ii,;.;;'."*f,, (skin resrs roruDerculln were repeatedlv neeative)Jhele ñndings "*'i, ai.'.r.", wrrh recentlypublished.data showing üai a CD3-(. il;?i;;li'il;icomparably small

"rnouñr oiruiu.. TCR failed to respond ,ior-¡o,Tl- l1?ftt¡ng

m,noclonars againsr rhe icrüco¡ ;;;ü;i": ]ffi :" ;iillüli,,..H:'tT..dmotecules are.expressed in the prasma memuiane in rb-ñ-ioliJin rnur,n. rnuran,i,lTr: $il defective tunction iugsotr. rn"iih.."-;;y üe;pffi;,"r ¡hreshord ofrLK expression below which ¡eprorirerai i ue responsf ; ióR ió'iT),1#ff.y,i,Ji:'+,¿ fffi:ñh jl, ::llfi :",:;proliferation sienats (such as -r¡C-D2. ph"rú';1;;il1[üi.

"ro rL_2) wasnormal. This.indicates thar rhe proliferátion mecÉanism ¡"-ión p T cells istunctional. including IL-2 receptor'exp*.ri." -Jil¿*iyntf,"."f

''Tsble 2 protiferarive

resF,<)nses ofTCR ID T lymphocyres.

MitogensPh!roh:rcma|ll¡lurininPhorbol ll M,vrisratc t I Acclalr

Monoclon¡l ¡ntiM¡esAnli-CD:Anr¡-('DlAntFl-i

AnligensTcr:lnu\ ¡r)r()i(lAlk)Bencic tlnph(,clrcs

Intcrlcukins¡ L-:

Normal

Normal

.Jli["T'¿fl ¿:.1til"';..1 *,.¿fn- T.Rindependenr srrucrures (e.s. rh]- I r or

i 91e *, r,";151+ .;; il ;i ¡5; r'.il, ff., [:i,If, i:il.X^i: #t¡i; j:;i:fl HT.Ily,fl";, j".T?,,f; -"""ÍéH,*1,;:f r;ltli,*i:il jla.,:."1t

l..CELL RECEPTOR IMMUNoDEFICIENCY

conlrast, mutants that have comparable levels of TCR"/CD3 expression, but contain

CO:-E ut well, had normal calcium flux responses. This suggests that minimal

tevets áf CO:-( are required for normal TCR-independent proliferation The case

of the mild ohenotvpe oi TCR ID offers a confirmation of this suggestion'- ñ"e"ráin't B lvábtrocvte function, the following results have be€n obtained: (1)

not-ál ..-"t .óncéntraiion of all tg isotypes except IgA, which is sliettly raised in

túe siblins with mild TCR lD; (2) normal antibody titers as a result of vaccination

in mild iCR ID (rubella) or infection in severe TCR ID (para-influenza,

i¿e"óui-r); (3) vaciination withoul abnormal sequelae with. attenuated measles,

-u-p., -6.itu and poliomyelitis viruses; (4) negalive serum isohemagglutinins in^

ih. iJuir. uut nor in ihe milá case of TCR ID. Siñce there is very low expression ofión i"iCn ID T cells, i( is difficull to envision how they may provide T-cell help

to ;;;¡t;; noimal specific B-cell responses in vivo' unless a quantitative TCRdefLt is oostulated. ihis "partial expréssion defect- correlates well with previous

p¡"notvpfu data, and rnuy állo* for üe -normal" triggering of TCR lD T cells and

;;;;;ái"raAái"ery of úelp to B cells under certailcircumstances (i'e iigh local

-iie; ;n""ntr"tion). Ir alio correlat€s with the presence of a normal fraction ofoeriilerJ úi."d- i lvrnp¡o.v,.. that express iuzs (l--z receptor) in .ivo.'s '

buairritarive differenies'in rhe number of TCR|." T lymphoc¡es would also

eiolain rhe existence of the severe and mild clinical phenotypes (see below)'-^'ru1

ótír.i."ii f*"ug", ir. funcüonally normal iñ TCn'lD. [n particular, normal

n r--U"t. -

-¿ f,rn"íiott of granubó¡es have been found (Perez-Aciego'

unoublished). lt seems t.asonáble to'conclude that the memhrane defect is

re-itricted to the TCR comPlex.

Smtcural Defect Underlying TCR Defciency

Due to üe multicomponent nature of the T-cell antigen receptor' the low TCR'/

óó3 ;"d;;r;;;;;ui"iuJ cour¿ have originated in delective svnthesis or assemblv

of any' of its components. Despiti the-low level ..

surface expression'

irn-unfpt""ipi,",ion *irh anti-Cp3 and anti{CR antibodies demonstrated the

"*¡ii"n.é of ütracellular complexes in metabolically labeled PBMC isolated from

!iui¡'i'"1,, -

ñ^ ;;J w. Howéver, while TCR/cD3 complexes from normal

i;;ñ;"",.. --contained both immature and fully processed N-linked

,íürái"1Jr,iii¿.i, -riiiii

puti.ntr. lymphoc¡es lacked the marure forms of üe

L-ñ-or"* Ítt.i"i.re, alihough thi iratieñts' PBMC were able to synthesize

i"rá'".füf "i ióúCb3 cofn-"pl.xe.. ihey tu.r. retained in inlernal organelles,

;;;b;üi" the endoplasmic reiiculum, aná did not reach the- cell surface' At this

;;ñ; ,ri.;;,ii ;riiuiing v precluded any lnor!.sqgiT^of.üis case' However'

í"""frJrl*úo f,"ui U"en-pertórmed with sibting D\ PBMC. lr.was found that the

.üoofur-i. TCR/CD3 complexes of siblings Drs T-cells lacked one of the chains:

Lñ'í-iliii*. ¡, panel B).'Since. in some murineru and human2r T-cell mutants

f""üri bo"iE, ihe' remaining TCR/CD3 complex-i1 91p91ed. verv inefficiently to

iii "!il

i.rf"Ji, ii is likely i-har association oi CO:-g with the other subunits is

.equiie¿ for their transport to the cell surface The direct irnmuno-precipitation^of

ból-i-*ilá ipiiini antiuooy showed that sibling D's -PBMC had CD3-6

ilá.'*h "i'áim"'isf*d

levels. This resembles some muiants of a human T-cell line

Hiñ-Xii:wiii;i;-á.o rt"¿ impaired assemblv of the cD3-6 chain with the TcR'/CD3 complex:r.

:....'' , ,ti:

i¡.:ii:.!'

E!9>5E

r;ig

'6

'5

,'E>f

.g€EE

r9 9

.€

q, "9

e7;

I a jJ >i¡5!

)¡!

IHE) F;

2lJ

.;p

¡t

E9

¡r¡l

t 0,t

l? r.

.;f

¡t&8E9

9E

9o

NF;

= e7,

;..:-z= E

'- ó.

ó 0.

2.= |

i.::¡c:t

¡Ei¡ 9::

? 5il.=F?gÉ

: -sE

<Fó

i.E 8

¡:E *iEÉ

=i 2.> 3I'E E

:iü :ó

tE ¡a

e.! b

99p ;;.: Ei E *.sB:iü5 É..i¡ E

"¡E S 3,r; *. ,i!!

'i€ 5 :l;3' E E!í 5¡P: -!

t o- E€9¿ A.,9 E É¡3E 9"í¡ ?*;ieE,'7íE; ¡i: :;-i-ó ssg:!;i;"c$iiEÉ *é< 3*;26.¿ÍE5R-E B-E;.i a.o "EÉr€;

_g iiQr:; É': r

ER &x.iF<:. r iEñ-.= iüÉ f:*

E-e€.¡ E'E:5t< sF! ¡¡=€83 á;=-;<;.ó.4ierT{E*É

;i*:É g"i É.2i.E.s,9=l);'.i8 Si's= :

ilá'¡:<-'.!2YlItEo B+'É E.'

EÍqEÉ!:9üssE

; L-9;É XE<:EeÍ.oEdr E:

ñt 3I óe4BÉ,E - 2))e:ii. ..Ei

:icr

.Ee

ó-:?

28,2=

i¿i.9

:6,

:= i, É.11o-I!&:ig:'i,:¡;3

EI<i2YdiÉi r¡

;.2)<lz'

ti

5:zl^!<{ci¿r!

Q!

t::<

t6

:ó6 :ó-

;5

;gl

O

9

G

Ee

z¿.

i!

*ilE¡

.Jtt

I

ri:.¡át

9F

*E

ix:-:,ú

t-

iq

E!9¡

orq9€

IO

8EIt

E

-rr

¡o=t

:lo

I ":¡l'.t.

aO

ioa

o

ir¡

!.:¡ll'l ' .\(, i,?,

:,'.' ,'j

T.CELL RECEPTOR IMMUNODEFICIENCY II

Northern blot analysis indicated that normal size transcripts for TCR-c' TCR-B

antl CD3 component¡ were expressed in the patients' PBMC' althoush the amounl

of cD3-t mRNA was uuout cóát lÑ"i iri sibling D\ than- in n-ormal PBMC

irrr""* ¡]ü"i n¡. ir,it "*rirut".

with a similar ieduction in the amount of CD3-

¿ 'ff;i; ü;;*i úv' i..unop.."ipitation' The expression of CD3-7 was also

áiririnished by about 5o%."'ü.t;;-ü|¡ot- anatysi" or genomic DNA digested with several restricrion

.;;;;i;";; ; áiiÉrencesf,etween normal anid patients'T lvmnhocvtes in the

numbe¡ and size of restriction;;;;;;i;;;;;;;p"nting t" coí-ai'' cb3-v'-and

éiii:l fñ.*""1t" er at unpublishid)' lt also shówed tñat TCR-B eenes had been

;;';il;¿5;;;á1""" ói'p'"¿á.i'iante áiricett ctones in the i'B-MC.populatior

ffi'ffiil: ^;;;;;É1;ú restrictio-n fragment corresponding to the variable

regions of TCR-É appeared as a smear"'The results obtained until nol'p"inr to üe impaired. association of CD3-( with

,h"';il; ilür;i,;;i ti" idÚcoS.omplex as tñe probable cause of üe defective

;;;;;;-"f-,ü.á.pi"* on ttre ,urtacá of T cells'and hence of their diminished

;ílt;";';t;;;ti. !ti..ri. The ultimate reasons fo¡ the defective assembly in

these patients" T cells are at present unknown'

Further Cases of Possible TCR ID

In addition to the two cases in the family studied here, olhe-r cases of possible TCR

ib;#'ü; ü;ea. se"et¿ iam iai ScID uariants with 'membrane defects" but

;,ffiJá;;;-áú;;;oii un¿ s.Ji' could be rCR ID (rable 1)' rhese patiens

with impaired T-cell function "ere

áettribea before the general availability of-arlti-

itn # _i:cbl -onoctonat a"tiu"¿ies, making rheii classification as TCR ID

uncertain¡o-oa."'X tü.n,rn ¿".cribed casea5 in which a patient had b-een-exDosed in utero lo

t.A,ii:'#J''"":;;ffid;;;üi'ulünldn'tionarrCR'/CD3'colpra:-PPlqirorn- rtti,

'p"ri.nt faited'to prólifeáte in response to .l83lds of the TCR'/CD3

;;;ü. 'fi;;.'ili t".ionJiJ to the aridition of PMA plus ionomvcin' a

.,#íil',#;t;;."iít.,rt'., rEÚcir¡ activation pathwav' IrnmunoprgciEqlpl

analvsis revealed no uppur"n, u-bnoiÁlity in the iomposition of the TCR'¡CD3

il;;i;;. ii;;;"i'i¡J-i"" üat üe cells were responsive to aluminum fluoride' a

;;r¿'ü;Ñ;i;; ;'f d-prot"i"f ináit"iti t¡ut the' defect in.these cells must be

iii.iliif . 'ü.,

i. -

Lnoin uUo,it -

áif,"i cases of tunctional deficiency. of T cells

!;;ffi!riziJ"uy"to* ,ect"rion Ji-j upon.activatiol of T--9ells with mitogens'

iliü;;;ilt'ñJ untiuooie.*.e. The T cells from these parients however, were

able to prolíferate ,r, .".pont" io trtá aJáition of exogenous'Il- 2 in vitroa6-a8 or in

iiü", fiJrl,iiiig ,nui trt! .*pttttio" of IL-2R (CD25-) was normal' In another case

th;;" ;;;-iuñihal defect in üe e-xpression of IL-2R and IL-2 secretion upon

;ffi;;iiññilMc *itr,.itog*.r.'rhe fact that the secretion of IFN-7by üese

l jiir *"ihrál.p¡red suggestsi defect in the TcwcD3 activation pathway'

CONCLUDING REMARKS

The obvious lack of expenmental models for the study of the immune syslem in

man makes the thorough cn"tá"i"tir"ti"" oiiD u ut"f.í, if not the only, approach

j..',.:::.''"til-:

12 S. ALARCON AND C. TERHORST

to.-th,e,ln vruo analysis of immune functions. This is specially true in a number of IDdrsorde¡s where rhe resoonsibte CgI:. or. gJles Iiu"" Ui,"n ij.nt¡fied, such asleukoc¡e adhesion defi ciencvi r, .A

on. o."r*i.".yn,- c1" i.hT,"n.y,r. ch ronicgranulomatous disease5a. etc. -Such

studias_ have -,yieidi

ricttr'inrigtrts into themolecutar basis of immunitv. Sinularty, TCR Iq-gil;;..."JJulru, tuntlamenlal:.:"::,!* on rhe biochemisíry, development un¿ t,n.ríon ot tie'humrn imrnun.system.

TCR Assembly and FCell Function

::I.Ffl;'ar.t¿.;

-:.i.

..

TCR ID and other narurallv occurri:rg variants may aid in elucidatrng the complexlisl*:l ,l1gisms invohed in úe syntheJis andiiiJi'.,iibn ro rhe r_celrbiochemical mecha¡isms i"í.t;;l i" ñ,.,ñrili á#".il#:,i+H ll",f:Tfflü,1fi : T.,# I:::l*"in".:.,1¡:."* *:, f ¡1. "ú ;iÍ;; ;;"; "... ( e.g C D 2.gD2q. r..I For ilsra¡-rce, tr," r".t tii"iin-,iujt ; u;ñü&""lTcrures

(e.s. cDZ,association_"f ct3-t'üi'lj," o¿,.. CD3 chains án.r rh.r ilt-"l,lT!:,,t^*association of CD3-f with fhr

-" -'-'.-'é u¡trc was an lmpalredcomDlexes harr immet,,,- *_,,-r-,ojll:.^^_9?J fl.rains .and ttrat ttre incáñp'r'et!complexes had immatu¡e N-ti*"a oiiloru".rr"riá"iñdii;i"r"lil iir'" *::3#:t;3l_9^?i;f^1, necessary for rhe expoi or trre rcúóói"Jri"l._ 1., r¡a ^Arl

- :_ ' .' ¡¡v!!erq¡, ¡v¡ u¡c s_rpoIl or me I UR-/CD3 comOleX to ¡he Cell*I*.-: f*:il T,i;9D3 ptus rl_2_driven i*.u jir. ¿á.i"áj lrom this sibtinothis siblinghas been obrained, and it exáÁses ro*. r.n"l, orlá-iiüét¡':t"ilHt?ii:f*.;;ll j,¿,::lf f.lhplf*L:,1,t3:_:.ti,r,i,ái,|ü_"."nJ*edrha,cD3_/*1".1f -,J,::lf re¡r¡i"cri,ñcJ-¿yi!'i"r"rirJ.:#;ü'_-.íj;:[a-s-1bfenr. indicatins,rhat CD3-yis oispeísauri ¡;;,h;iiiffi;;Til",ttüti;]lxeguerro er a/. unpublished).

7: Lymp hocyte Deve lopmea

:lit:^"., -qoth posirive. (torvards

.¡elf-trlt{^5coglution) and negarrve (toterance)selectron requires the interacüon of TCR wi-th -'I\,iitd;:,"';r

sel.T antisens.respecdvel¡ ir will be of interest to test w[elLer th" ior"i"""l, if TCR "*prorion*::," 1wlc resrricrion, in these cases of TCR D.-lñ;o;;iül"run"" iriductionmay have caused rhe auroimmune.fe¿turej of severe fcn ió inul. il,ilü;ithe hisher TCR expression h

^19 TCI lit;;y- ;;d"?r normal negativeserectron mechanisms. In addition, ir,._ u.

"on"iuáJtirái ¡ol ,u.r"". TCR didnot affect the differenüation of thymocytes ¡ro matur."'bp4 o¡ CDg Ttymphocyres. Both selecüon and difí,ere;ú;;;"- ;iüil;; rhymoc¡es intoma-rure CD4 or CDg T cells appdiff erenriarion_orr."lt"ln-ffi '#.!"_J#i**,*:t,.'ff fff ,ff frTSrower surface TC_R levets. and rhus rake pñ.. ;r;li.; ;;;;;";; than selecrion. In¡tus scheme, CD2. CD28 r"rg.r ,rruttu.., oi-'d_i'"át"iá, u. rhe requiredjii:Hjlit?:?Tüifi"üi3ñóil:ü:"til:,"fi.it"i"n:'*"tm:n*oeve¡opmenr of lymphoid iissu¡s.ls se'verely affecü'l,i iói n (Table I ),::fryj:_lC oüers',susgestionsso.nn.üat antigen-stir*l"ti""'*j i.¡licular lymphoidceu rnteractrons (trorh takine ptace

. thróugh Tc[-;d iñ"r;;ü;,rtilfiil;

:'¿n'::"t lTf*1rucrures)aie ó'u.u ro' u8ii' ó¡-i''i"'i'.i.:""¿í.y rvn'p-¡"ii

SCID Classification and Therapy

*..^"9d-ii* TCR ID -has shed some

. Iighr on the classificarion of SCIDóI , anererogeneous group of disorders that sha;e u

"ornron "linilui iicture, but whose

was absent,

43, t33-t92t2. Matis. L.A.. Fry. A.M.. Cron. R.Q..

S¡ruclure and specilicily of a class II245,716-119

T.CELL RECEPTOR IMMUNODEI'ICIENCY

Collerman- M.M.. Dick. R.F. ¡nd Bluesl()ne. J.A. ll9l{9)MHC alloreac¡ive yó T cell recepkx helerodimcr' si-rer¡(e.

underlying biochemical defect is often unknown. [t is apparent from the prestdata that -further variants involving abnormalities at any biochemical step in TCRassembly and/or function will likely he described, as has been accomplished in the

better-srudied B-cell system6:. Indeetl, a lhree-year-old boy with low expression ofthe TCR¡CD3 compiex on the plasma membrane of resting and activated Tlymphocytes and with a very moderate clinical abnormality is being studied (AÉisiher, bersonal communicátion) and may be considered as a mild form of TCRID. The irolecular basis of this particular TCR ID is unknown and may be differentfrom the cases of siblings D and Y since the patient's T cells respond to,antigensand allogenic cell stimulibut not to lectins or to CD3 and CD2-specific antibodies.

Lastly, the elucidation of the basic mechanism of TCR ID may offer the chance

of corréctive somatic gene therapy by transfer of recombinant retroviral CD3-fconstnlcts into hematdpoietic stém cells' as is presently being done in other ID(leukocyte adhesion d'eficiencyó3, chronic granulomatous diseasesa and ADAdeñcienc/a).

Acknowledgeñenl

The autho¡s wish to thank M. Lop€z-Botet, M. O. de Landazuri, P Culierrez, M. Ferez-Blas, M. Timona¡d P. Bleiche. for help and discussion, and J. Manzanares fo. referring the patieol lo us B.A is the

holder of a Special Felówship from the Leukemia Sociely of America. This work l,as suPported in Partby FISS, CICYT, NIH (At- 150ó6, AI- 17ó51)atd NATO (31 I /88)gtants

Relerenes

L Rosen. F.S.. wedgwood, RJ.. Eilb. M., A¡uii, F., Cooper, M.D., Good' R.A.' Griscelli. C.. Hanson'L.A., H¡lzig, w.H.. Matsumoto, S., Seligman, M., soolhill, J.F. and waldrnann' T.A. (1986) Primaryimmunrüeñciency diseases. Repor¡ of a world Health Organizalion scien¡ific Croup. ('ltlicolI mmunologt arul Imnrunopatholog, 40, 166- 196

2. Klein. J. ( ló80) Complemént and óther activation systeús ln Immunolo&| The Sciente ol Sell'NonSetI Dis<ñminutio¡,edited by J. Klein, pp. 310-346. New York: John Wiley

3. Rrxen. FS.. Cooper. M.D. ind wedgwixrd. RJ l l 98'll The prim¿ry imrnunodeficicncies r firs¡ oftwo partsi. N¿,9 En8l¿,| d Joumal oI Me.lic¡ne,3l l, 235-2{2

4. Payne, R.. Brodskt, nM., hterlin. B.M. and Young, L.M. (1983) "8are lymphocyte ' wrhoülimmunndeficiency. Hrtman Irnmunolo*/. 6,2 | 9-221

5. Hi¡schorn. R-. Roegner. v. Jenkins. T.. Seaman. C.. Piomelli. S and Borkow\kv. w /19791

Erythrocyte adeÍosine deaminase deñciency without immunodeficiency: evidence for an unestable

mútant enzvme. Jo¡¡¿ al of Clinicol Investixa¡¡oa ó4. I 130- I 139.

6. Rosen. F.S.. Crpper. M.D. and Wedgwoo¿. RJ (198{)Th€ prinary immun0deñciencies lsecond oftwo partsr. ñ.r' Er8¿r¿d lournal oJ Medicine.3l I. 30(l-3 l0

7. Oetlsen. H.C. and Terhorsl, C. (I987) The 'l-cell receplorrl3 comp¡ex and T-lymphocy¡eactiialiott. H u man ImmunologL lt, 1 87 -2O4

8. Clevers. H.. Alarcon.8.. Wileman. T. and Terhorst. C il9lt8)TheT-cell recepk)r/CD3 complet a

dvn¡mic prolein eÍsemble. Annuol Rerie\s of lnmúnok$'.6.629-6629. Té¡hors¡, C.. Alarcon. 8.. de Vries. J- and Spi¡s. H. (1988)T lymphocy¡e recoSnilion and activalion'

ln Moleathr lntmunologt edited by B.D Hames and D.M. Clov€r. pp. l'f5-188. Oxford: IRLPress.

10. Slr()min8er. J.L. i | 989) Devek)prnenlal bi()k)gy ofT cell receP¡)rs. -li?¿r( P.244.9'13-9'19I l. Brenner: M.8., Strominger, J.L. and Krangel, M.S. (1988) The 7d T cell receptor. Ad\', lmmunol.

t4 B. AL,A,RCON AND C. TERHORST

l.r. M{tdin. R.L.. Pirmcz. C.. H('fm¡n.-¡.M.. n)rigi¡n. V. (tvcmuril. K.. Rc,¡. LH.. Bl¡xrr¡. tt.R. ¿nLl

,",1*ffÍ;,Li;,iJ:",1...¡¡X1.¡¡.ililf1$*.;;ü;+iil;';; i .iu'"i"."puo, accumüra,e in,{. \, nflcn. K.L.. Hxpp. M.p. Da ü\. A.. palmer. L.. Kuho. R. ¡nd tl)rn_ W.K. r | 989 ) Stimulali()n of ¿

- l'?,.o|)i!);,:lry,li,iil,Y:;,,Ti:::'f.r ""rr'"."p'.i' vJ lv"on "n,ig"n derived rr{,m

ll il,i¡il! $,1r1;.?j';i;,x,ilün.?l;#Í,#,1*ll;"?.y;i,lllilt:t;1:;10.',0 ' *,,.,"

t6. R,rce i. S.. Brenncr. M. Creenrrrin. t.r. n¡l¡. S.p- ieirr,,;.i: tp:;.,, Bteicher. pA. te¡j,.,.

hTf['}i'J, $,,il'5srer{or -D'|ffereniiati;;-i^ ";.;e;^ ';;';;;"1 üiio co¡ cykr},ic r

17. B¡nitash. M.. Ca¡ci¡ l\4r¡r¡ler. F

;-Éj;[*lS}tr1¡;[#¿in,Jl,,ii",'trt'..1,;';;;l;Tt;t,"',?#.fJ",l.i*"i;l;l;,',*'' i;l'ü;1,il:ii'i1..'";;:",'il,i1l..iTi,"k';1fl;X..,';i;Ji";".y1;,1["];ll{yf,:;j,f;;19. Weiss. A. and Slobo, J.D. (t 9¡14) Requiremenr f(,r rhc coexpressi()n of T3 and rhe T cell anrigen,,, :i""ifi::iil.1Jlil''il:'il:l1ll,",ti'ff:,;" Jl;h1iS;llii,ii;3,,",_, (. and A,arcon. B( I9ll9) HTLV- l prevenrs cell surf;

., ft?urarr('n^or rhe cD3-y. ó. €and (T:":iL'ff#1,,:lln' t cell recepro¡ ror anrisen rr'."ush ¿u*n-' l^l!!i:.,.,s?r':.il;,i:_";u'.'_.";1".J"".;",,p,Iffi;i

,,!?lll"t*":ili,1"::,f"ifl*ff:i

:tT:lü:_iil;'" "e cD3-v-d-e core and singte'r ceu *."¡.''

" 0"ü"p

"r,"¡" s. t. Biot. chem..

12. Weissman. A.M.. &)nifacinl). J.S.. Klausner. R.D.. S¡mc,lsr¡n. L.E. nnd O.Shea. J.J. r¡98qrT_ce

". iili:¡i'::Tj.'i:É:li:*::;i';T!i;:|"ft:l!X? '"

n" v"'iin. ii""-,,íaos ic¡i. "¿¡,"d'i"" iiljii;'¿^t-l1ii";*.I;H.i.li::,1:'t' c ' Br;mbcrg R . Ararcon. 8.. ceha. R. ¿nd rcrhor\,. c.

,1 comperenr TcR/co3 "o.0,.*"r.

, uJlll

3ffi'li$.'il'r; tu'^'u..'ut"'n ot cD3-l int. tunctionaliv

" ",;.;Tl".; ,a$f."t1.Til1i; li,[Tlii J;i:li.:lilül;i ;ijii] !lj"!,J;,:,rui:::

tt *J;.ti;;:il¿5ii;:i:'j;;l;"1':':'' F- Kutb R' sv Ms and rcrhorst. c 0erie) surrace

- rri,m ¡ p,r\r.ER rran\F,rr h¡,,"r ,,,i!r',i,11,,:;;!ri'::,t{ape or incomprere rcn. co: .'.ii.-.,

:o. we'ss.A.rmbqren,r..Hardv.K..^,ilJf}"?;:l|;j;;,;#on.rl"rn_.0,|;,"r" rheK,rcor¡nr,sen

,, lfi3:'í:^T81*l I ::if ;ll:-.. membrane (ú humon r ry-pr,""y,...'t,fL}5';a"...,l||,":'.'.t.1't

inos¡ol ¡ .'¡.s-triphosphare in p¡asmatt

'jilfld;:i lili canr'il o ¡. I l'Jtc) rin"i.. ana pr,uspt"ra.es in T-cer¡ acr¡varion. 1¿¡,r¡.r¡o¿

29. Sterweis. PC. ¡nd Cilrnan. A.C. ( t !

.,¡:-ri$:l¡.:#¿ü:;,;:.;:i*f;'qry**t1fl j,.illffi tff :ff ;::ii:Xl;H:I]i',ff l;;l|;¿:11;.;l['r'¡i' pt"'pr'.'i'i"tül.,i'"-p.'iv]priie'associa¡e¿ *¡,r r¡é r

'.' ;i:;],T"?::}T:!Ili-t;:;ilt K¡¡usner' RD 1re87i Murripre kin¡¡ses.nd sisnar rransducr¡('n. r.

': ll91: c F- Trevillva¡. J M.. Dalgupra. J.D.- wong. L.L. and schkrssman. s.F. r¡ 988) The cD4

". ffi"#:l:,L:',',lf i;i:.,Í;'ili'i,i*lT!:'.;",,¡-¡ii'--i;!'iiil$',oi',i r.,m hum¿n rrJ.

^verlle e. 4.. Boolma¡. M.A.. H¡rrak, E.M. and Bolen, J.B. ( l9tj8)The CD+ and CD8 T cell surface

1ili*jrlj.* *. associared \rirh rhe inrcm;rt ,"'n¡.nn. ,".,,ii*1p.,,i.'iliii'i',." psr,",. <i,n rs.

34. Regueiro. J-R.. Martin-Vi a. J.M.. Solelo.-T--Ere-¿-Seoane. C.. Manzanares. J.. perez_Acie8o. p and+jlffi;Yl!',1;"1;Jl}e)

Autoimmune enteroparlv in a .etecri.,e aiieci iii.-u',ru.. unrigen-.p."in.

T{ELL RECEFTOR IMMUNODEFICTENCY l5

36.

311.

39.

17.

Regueiro. J.R.. Lope¿-Botct. lvl.. Ort¡z dc Landazuri, M.. Alcami, J., Corcll, A.. Martin-Vill& J.M..Vicario. J.L. ¡nd Arnaiz-Villcn¡. A. ( lglt7) An rr¡ ri|rt functiond immune syslem l¿ckirg fxrlycktnal-Fccll \urf¡cc .rprcssi()n of thc CD-]/Ti (WT3l ) complex. Stttrulinavion loumal ol lnununolo¿¡^.26.6r)9-7t7Rcgueif(). J.R.. Lopcz-t otct, M., De L¡ndazur¡. M.O.. Alc¿mi. J., Corcll. A.. M¡rtin-villi! J.M..M¡rlincz-Laso. J.. Pcrcz-Aciego. P. Vicario. J.L. ¿nd Arn¡riz-Villena. A. I ¡988) A novel fx)¡ycl()na¡'[:cell reccpk)r cxpres:iif,n defect prohi¡hly not linkcd k) HLA. lN lnmunob¡olog, oI HIA ll.l rnnu rkrlar'rtr\it \ M¿ lli\k\\)t,tputihilitr: cdited hv B. Dun()nt. pp 555-556. New York: Springer-VcrlagAlarcon. 8.. Regueiro. J.R.. Arnaiz-V¡llcna. A. and Terhorst. C. ( l9ttll ) Famil¡al defect in lhe sulacecxpression of the f-cell receplor-CD-3 conplex. Natt Englun¿ lournal oJ ive¿¡cin¿. f,19,| :03- I :{HRcgueiro. J.R.. Arnaiz-Villena. A.. Orliz de Land¿zuri, M-. Mdrtin-Vill¡. J.M.. Vicari(), J.L.. Pascual-Ruiz. V. Cucrr¡-Ccrcia. F..

^lcami. J.. Lopcz-8olel. M. and M¿nzanarcs. J. i 191t6) Fami¡ial defecl

of CDI ,T.3i crprcssion hy-f cclls associrtcd wilh rnrc 8ut cpilhel¡al cc¡l ¡ulomtibodies. ¿-¡¡f¡cr¡. i,I l7{- r 175Sussman, JJ,, Bonifacino, J.S., Lippincol-Schwartz, J., Weissman, A.M., Saito, T., Klausner, RD. andAshwell, J.D. (1988) Failure to synthesize the T-cell CD3-zet¿ chain: structure and functio¡ of aoartial Trell receDtor complex. Cell 52, E5-95huckler. R.H.. Cithcrr*'n. R.8.. Schitf. R.I.. Flrrcir¡. 8.. S¡rnan. S.o. and waldman. T.A. {197ólHctenrgeneity ol lymphocy¡e subp()pul:¡ti()ns in severe comhined immunodeficiercy. Evidence¡gainsr a stem cell defect. ¿ ( 7¡¡. ,h¡rcst.. 5t, | 30- l3óCehrz. R.C.. McAuliffe. J..1.. Linner. K.M. and Kersey. J.H. (l9tto) Dcfcclive ñembr¡ne func¡ion in

p¡tient \ ith \cverc comhincd immun(xlefrcicncv. ('lin¡r'ul M¿ Í.tPüinr.nkl ln.,rtttttohtgr.39,3.r.r-J.r8Celt¡nd. E.W. Ol¡ver. J.M.. Schuurman. R.K., Matheson. D.S. a¡d Dosch. H.M. (19791 Abnormallymph(rcyte capping in a p:rlient with sevcre combined ¡mmunodeficiency. ,\ew €tE¿./. .tre¿.301.I l.l5- I l{9Kcrscy, J.H.. Fish, L.A., Co¡. S.'1. and Augus¡, C.S. ( 1977) Severe combined immunodef¡cicncy withrcsponse to cafcium ¡onophore: a possible membrane defecl. C/¡¡¡. Immunol. ImmunopathoLl.62-ó8Rr$ell. B-R.. Bu¡sr. N.R.M. rnd Stcnzel. P il9N2l An X-linked \tndrome of diarrlxt¡.p()lyendochrinopathy and lat¡l ¡nfection in enlbcy. !ournul oJ Pe¿iutry.lOO,7 3l-7 37Chatila. T., Wong, R., Young. M.. Miller, R.. Terhorsl. C. and Geha. R. {1989)An immunodefic¡e¡cych¡r¡cterized b!, defec¡ive signal transducli()n ¡n T lymphocytes. rvew Enghn¿ Journal oI 'lÍe¿lkine.f20.696-701Lopez-B{fcl. M.. Fon¡an. C., Rodriguez, M.C. and De La¡dazuri. MO. il982l Rel¡¡iorKhipbct$een IL-: synthesis und ¡he proliferative response to PHA in different pnmarvimmun()dcficicnces. 1 /lñnú nol.. 128, 67 9-683l'k)menhcrg. N.. welle. K.. Merlclsmann. WR.. Kerman. N.. Ckrhamu. N.. venül¡. S.. F¡ldmm. S.Kruger. C., Kirkpatrick. D.. Dupon¡. B. ¡nd O Reilly, R. (l9tt3) Immunologic effec¡s of inlerleukin :in primary ¡mmunodefic¡ency diseases. I /r¡rutnol.. llO,2614-265t)Saiki. O.. Shimizu. M.. Sacti. Y. Kishimolo. S. and K¡rhimok). T. rl9l{-¡r Dissociation ¡n lhcpr(xlucrion of B-cell srimulating faclors (BCCF and BCDF)and intcrlcukin I by l cells fr('n a

common variab¡e immunodeficient pa¡ient. ¿ lmmunol.,133, | 920_ 1924

Pah$a. R.. Chalila. T.. Pahwa. S.. Paradise. C.. Day. N.K., Geha. R.. Schwartz. SA.. Sl¿de. H.'Ovaizu. N. ¡nd Cood. R.A. llgllgr Recombinant interleuk¡n I ther¡p! in \cv!'re combined

immunodef¡ci€ncy disease. Pro¿ Notl. Acu¿. Sc¿ ¿'5Á. tó, 50ó9-507350. Doi. S.. Saiki. O-. Tanaka. T.. Ha-Kawa. K.. Igarashi. T. Fuiita. T.. TaniBuchi. T. and Kishimolo. S.

( | gtttt) Cellular and genelic ¡¡lalyses of lL'2 p.()ducli()n and lL-2 recep()r exPression in ¡ pall€nt

\¡ith famifi¡f T-cefl d()min¡nl imñunodeficicnc\' (lin.lttttn nol lnútutttoPa! hol.. 46. 21-3651. Kishimoto. T.K., Hollander, N.. Roberts, TM, Anderson, DC. and Springer. tA. {l9li7)

Helerogeneous mulations ¡n lhe beta subunit common lo the LFA l. Mac I and p 150. 95

glycoproteins cause leukocyle adhesion deficiency. C¿l¿.50. | 93-20?5:. Tischfield. J.A.. Creagan. R.P. N¡chols. E.A. and Ruddle. F.H il97'¡r As\i{nmcnt o[i qene for

adenosiri€ deaminase to hum¡n chromosome 20 HumanHerc¿iry,24'l-ll.53. Hauplmann, G.. Tappeiner. C. and Schifferli, J.A (1988) Inherited deficiency of the fo.,r¡h

componenl ()fhuman coñglemenl lnmrnodei( iencj' Reviews. 1,3-2254. Dinauer. M.C. and Orkin. S.H. llglltl) Molecular gencl¡cs of chronic gr¡nuh)m¿lour da$a"ie'

I mmunodel¡ciency Rev¡e w¡ l,55-ó9

.lL

J-3.

J{.

45.

.16.

.19.

t6 B. ALARCON AND C. TERHORST

55. Shtl..l'v'C. Ncts,,n. (..A. Nc\^hcrrt. l:lrl Kr,,n1, l).M. Russclt. J.¡.t. ltnd t.oh. I).y.1tefi8tR)s¡livü,. il:,1':i1';il*::jX]";:liill ll:i",$"ll('r¡,n I (c¡r\i¡.,r,,n\sc"¡.",i... ,iu,""..r.r0.z¡_ro

...q*,;;;;;;;;,;;;:.;iil;:.i;,,lit.:;il.:::;ilT.;,i;l;ll,;,1,ii,il:ffii,lill,,:l"Tilil:ff:lll

" iill;i{-.ilJ'lill!:;,1;::t:tÍ,:iJl;::iIT:ií,,y;i:',""i1.:'filT,xl,i-lr:lJ,:r'.iT;,rl

58. Rcinhcrz. E.L. ( l rSS ) A molccular basis f()r lhymic sclecti(u: regu¡ali()n of T¡ |

,, :iilf,:t:1fri5ff.*im;ii*li..,*h* ntilri*f ::;_;1,_.. sencr¡,ri()normaru,"r.*¡ii.¡,,í,,-,ljl¡,|);l"i.j:::l;'lrT]i,|cmcnt"rrherr-:p,'n"al';rrr"''' l:iili"l. *t:iiHiJ. ill:'illi;.i;-l)"')ir" u vi'""ui ¡. va,sud¡. r.. N¡ik,. M. r¡r,,h¡sh¡.

^, lül:rif iü:'ilyll*lü:*i*ü¡]#i;,)l;:'i$.Yl :i; H 'l/'i'{ s(\.'r( hlP 'n:'|''" "'r¡ell9)pft,gresriinrheclu..ifi"r,i,,n,riltonot"s' l.-' Ca¡cia-Hernanclez' C. and Arnaiz-villena. A-,'. ftll!!,¡t'llr;;il''11;:il,i"l,l;l;ili#.::*.:T?:#ff1';,1,.i:,:::;:,,,,,iiíi;:,:,i;,;::;j;,1,

ó.1. AndÉr\on. D.C. rnd Sprinscr. tA.{t9lt7r I p,,!,_.,- -¡!..-:_ _ , -,,_ niju:,li:"*lji,l$i.,,.;,i;l;,Jl1Tr",.;ilff'J;"y,llj,:t ,,*i:":.J:f;,,1,,;f.,ir"r

a"r.", in

immunodcr.icicncies .,r,,,,,,,i,tni;,,¡i:l,"lilil),;1,."Yirii'li,li Pr{'\pccrs ri,r {cn. rhcr¿pv in