REVIEW ARTICLE
published: 26 Janua y 2015
doi: 10.3389/ immu.2015.00015
Fi e laye s o ecep o signaling in γδT-cell di e en ia ion
and ac i a ion
Sé gioT. Ribei o, Julie C. Ribo and B uno Sil a-San os*
Faculdade de Medicina, Ins i u o de Medicina Molecula , Uni e sidade de Lisboa, Lisboa, Po ugal
Edi ed by:
Die e Kabeli z, Ch is ian-Alb ech s
Uni e si y Kiel, Ge many
Re iewed by:
ShoYamasaki, Kyushu Uni e si y,
Japan
Be nha d Mose , Ca di Uni e si y,
UK
*Co espondence:
B uno Sil a-San os, Faculdade de
Medicina, Ins i u o de Medicina
Molecula , Uni e sidade de Lisboa,
A enida P o . Egas Moniz, Lisboa
1649-028, Po ugal
e-mail: bssan [email protected]
The con ibu ions o γδ T-cells o immuni y o in ec ion o umo s c i ically depend on
hei ac i a ion and di e en ia ion in o e ec o s capable o sec e ing cy okines and killing
in ec ed o ans o med cells.These p ocesses a e molecula ly con olled by su ace ecep-
o s ha cap u e key ex acellula cues and con ey downs eam in acellula signals ha
egula e γδ T-cell physiology. The unde s anding o how en i onmen al signals a e in e-
g a ed by γδ T-cells is c i ical o hei manipula ion in clinical se ings. He e, we discuss
how di e en classes o su ace ecep o s impac on human and mu ine γδ T-cell di e en-
ia ion, ac i a ion, and expansion. In pa icula , we e iew he ole o i e ecep o ypes:
he T-cell ecep o (TCR), cos imula o y ecep o s, cy okine ecep o s, NK ecep o s, and
inhibi o y ecep o s. Some o he key playe s a e he cos imula o y ecep o s CD27 and
CD28, which di e en ially impac on p o-in lamma o y subse s o γδ T-cells; he cy okine
ecep o s IL-2R, IL-7R, and IL-15R, which d i e unc ional di e en ia ion and expansion o
γδ T-cells; he NK ecep o NKG2D and i s con ibu ion o γδ T-cell cy o oxici y; and he
inhibi o y ecep o s PD-1 and BTLA ha con ol γδ T-cell homeos asis. We discuss hese
and o he ecep o s in he con ex o a i e-s ep model o ecep o signaling in γδ T-cell
di e en ia ion and ac i a ion, and discuss i s implica ions o he manipula ion o γδ T-cells
in immuno he apy.
Keywo ds: γδT-cells,T-cell ecep o ,T-cell cos imula ion, cy okines, na u al kille ecep o s
INTRODUCTION
γδ cells endow he T-cell compa men wi h a apid, inna e-
like eac ion o insul s, which places hem in he a e en phase
o he immune esponse. Namely, γδ T-cells a e esponsible o
“lymphoid s ess su eillance,” i.e., sensing and esponding imme-
dia ely o in ec ions o non-mic obial s ess wi hou he need o
clonal expansion o de no o di e en ia ion,in synch ony wi h p o-
o ypic inna e immune esponses (1). C i ically, his implica es γδ
T-cells in in lamma ion (2), au oimmuni y (3), in ec ious diseases
(4,5), and umo su eillance (6–8).
Many o he s udies elucida ing he physiological oles o γδ
T-cells ha e been pe o med in mu ine models, whe e a majo
b eak h ough has been he iden i ica ion o p o-in lamma o y
subse s na u ally p oducing ei he IFNγo IL-17 (9–11). Mo e-
o e , hese s udies ha e been g ea ly acili a ed by he iden i ica ion
o cell su ace ma ke s ha seg ega e he wo unc ional γδ T-
cell subse s: CD27, CD122, and NK1.1 ma k IFNγ-p oducing γδ
cells,whe eas hei IL-17-exp essing coun e pa s display a CD27−
CCR6+pheno ype (9–11). Mo eo e , he wo subse s show dis-
inc Vγchain usage in hei TCR epe oi es, wi h a bias owa d
Vγ1 among IFNγ-p oducing γδ cells, and an en ichmen in Vγ4
and Vγ6 in IL-17-p oducing γδ cells (12).
In humans, γδ T-cells a e p ima ily iden i ied by hei
Vδchain usage, wi h Vδ1+cells p edomina ing in he hy-
mus and in pe iphe al issues, while Vδ2+cells (mos ly
co-exp essing a Vγ9 chain) cons i u e he majo i y o blood-
ci cula ing γδ T-cells. Bo h human γδ T-cell subse s a e highly
p one o sec e e IFNγ, bu IL-17 can be induced in highly
in lamma o y condi ions igge ed by in ec ions (13) o umo s
(14,15).
In bo h mu ine and human γδ T-cells, unc ional esponses
a e ini ia ed upon ecogni ion o an igens ha a e likely induced
by s ess signals and sensed by ei he T-cell o na u al kille
ecep o s. Some γδ T-cell popula ions a e also pa icula ly espon-
si e o cy okines o inna e oll-like ecep o (TLR) agonis s (16,
17). Following p oli e a ion and e ec o esponses, he e u n
o homeos asis is con olled by inhibi o y ecep o s. He e, we
discuss he a ious laye s o con ibu ions o T (TCR and cos-
imula o y/inhibi o y ecep o s), NK, and cy okine ecep o s o
he ac i a ion and di e en ia ion o e ec o γδ T-cell popula ions
in mice and humans.
SIGNAL 1: T-CELL RECEPTOR
The γδTCR complex is composed by he γδTCR i sel and a -
ious CD3 chains ollowing he s oichiome y: TCRγδCD3ε2γδζ2
in humans and TCRγδCD3ε2γ2ζ2in mice (18). The assembly o
aγδTCR complex in hymic p ogeni o s has immedia e conse-
quences o γδ T-cell de elopmen . The“s ong”signals s emming
om he γδTCR (when compa ed o he “weake ” p e-TCR sig-
naling) d i e γδ/αβ common p ecu so s in o he γδ lineage (19,
20). These“s onge ”γδTCR signals associa e wi h inc eased phos-
pho yla ion o ERK1/2, abundan calcium elease and induc ion
o ea ly g ow h esponse (Eg ) ansc ip ion ac o s (21,22).
The TCR complex does no p esen in insic kinase ac i i y
bu he in acellula signaling is ini ia ed a e phospho yla ion o
immuno ecep o y osine-based ac i a ion mo i s (ITAMs) in he
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Ribei o e al. Recep o signaling in γδ T-cells
CD3 cy oplasmic domains by he S c- amily kinases (SFKs) Lck
and Fyn (23). The ec ui men o hese SFKs o he TCR complex
in γδ T-cells emains obscu e since hese cells do no exp ess he
CD4 o CD8 co- ecep o s, which ha e been shown, in αβ T-cells,
o be esponsible o ec ui ing SFKs upon αβTCR liga ion (23).
None heless, he impo ance o SFKs in γδ T-cells is unde sco ed
by he subs an ial phospho yla ion o ERK upon inhibi ion o Csk,
a po en inhibi o o SFKs (24).
SFK-media ed phospho yla ion o he ITAMs on CD3 chains
allows he ec ui men , phospholyla ion, and ac i a ion o Zap70
ha acili a es phospho yla ion o he sca olding p o eins SLP-
76 and LAT. This lead o he o ma ion o a sup amolecula
signalosome ha ec ui s he phospholipase PLCγ1, esul ing in
p opaga ion o downs eam signaling e en s (22). He e again, γδ
T-cell signaling is di e en om αβ T-cells, since mu a ions on
he binding si e o PLCγ1 on LAT esul ed in a se e e block in
mu ine αβ hymocy e de elopmen while γδ T-cell numbe s we e
only modes ly educed in he hymus, in es ine, and li e , and
emained no mal in he skin. Unexpec edly, a popula ion o γδ
T-cells in he seconda y lymphoid o gans in hese mice unde -
wen uncon olled expansion and caused au oimmune pa hology,
sugges ing dis inc unc ions o LAT/PLCγ1-media ed signaling
in subpopula ions o γδ T-cells (21,25).
In humans, he majo γδ T-cell subse in he pe iphe al blood,
Vγ9Vδ2 T-cells, a e uniquely and speci ically eac i e o sel - and
o eign non-pep idic phospho yla ed in e media es o isop enoid
syn hesis –“phosphoan igens”o “phosphoagonis s” (P-Ags) (26–
28). These P-Ags we e shown o igge bona ideVγ9Vδ2 TCR sig-
naling in a ious s udies. Cip iani and colleagues showed ha he
ac i a ion o Vγ9Vδ2 T-cells wi h he P-Ag isopen enyl py ophos-
pha e (IPP), induced apid and pe sis en PKC-dependen phos-
pho yla ion o ERK1/2, p38 MAPK, and JNK, esul ing in NF-κB
and AP-1 ac i a ion as well as he elease o MIP-1α, MIP-1β,
IFN-γ, and TNF-α(29). Mo eo e , P-Ag s imula ion and CD3-
c osslinking p oduced iden ical phospho yla ion o he signaling
p o eins Zap70, PI3K, LAT, ERK1/2, and p38 MAPK (30,31); and
induced highly sus ained calcium signaling inVγ9Vδ2 T-cells (32).
Impo an ly, ac i a ion by P-Ags is he basis o cu en cance
immuno he apy s a egies in ol ing Vγ9Vδ2 T-cells (33).
Recen wo k has p oduced some puzzling esul s on he ole
o he γδTCR in he de elopmen o e ec o subse s o mu ine
γδ T-cells (34–36), namely, CD27+CD122+γδ T-cells p oducing
IFN-γo CD27−CCR6+γδ T-cells making IL-17 (9,10). Fi s ,
Chien and co-wo ke s showed ha T10/T22-speci ic γδ T-cells
equi ed hymic exp ession o hei TCR ligand o di e en ia e
in o IFN-γp oduce s, in con as wi h “ligand naï e” IL-17 p o-
duce s (9). Consis en wi h his, TCR-dependen hymic selec ion
was also shown o se he unc ional po en ial o dend i ic epi-
de mal T-cells (DETC) p ogeni o s away om IL-17 p oduc ion
(37). Fu he mo e,pe iphe al IL-17-p oducing CD27−CCR6+γδ
T-cells we e shown o expand and p oduce IL-17 independen ly
o TCR ac i a ion (38). Howe e , a subsequen s udy by Chien
and collabo a o s demons a ed ha a subse o phycoe y h in
(PE)-speci ic γδ T-cells p oduced IL-17 speci ically upon TCR lig-
a ion (39). Mo eo e , a ecen s udy by Hayday and colleagues
sugges ed ha an impai men in Zap70 signaling (in SKG mice)
mos ly a ec ed he de elopmen o IL-17+ a he han IFN-γ+
γδ T-cells (40). The au ho s u he p oposed ha “inna e-like”
γδ T-cell popula ions, including IL-17 p oduce s and some sub-
se s o IFN-γp oduce s, ecei e s ong TCR signals du ing hymic
de elopmen o become hypo esponsi e o TCR s imula ion in he
pe iphe y (40). Fu u e esea ch should aim o esol e he appa -
en con adic ions o he a ailable da a, namely, by cla i ying he
equi emen on TCR ligand engagemen , as well as he de elop-
men al e ec s o manipula ing dis inc γδTCR signaling pa hways
and hei downs eam ( ansc ip ional and pos - ansc ip ional)
mechanisms on γδ T-cell subse s.
SIGNAL 2: COSTIMULATORY RECEPTORS
A se ies o T-cell cos imula o y ecep o s a e known o induce
quali a i e and quan i a i e changes ha lowe ac i a ion h esh-
olds, p e en “ane gy” and enhance T-cell unc ions. Typical cos-
imula o y ecep o s a e ype I ansmemb ane p o eins ha can
be di ided in o wo g oups, based on hei s uc u al cha ac-
e is ics: immunoglobulin (Ig) o umo nec osis ac o ecep o
(TNFR) supe amilies. Ig supe amily membe s ha e a a iable
Ig-like ex acellula domain and a sho cy oplasmic ail, whe eas
TNFR amily membe s p esen ex acellula domains ich in six
cys eine epea s (which o m disul ide b idges) and a mo e com-
plex cy oplasmic ail [ e iewed in Re . (41)]. These wo main ypes
o cos imula o y ecep o s display di e en modes o in acellu-
la signaling: whe eas he CD28 amily membe s associa e di ec ly
wi h p o ein kinases (like PI3K o ITK), TNFR supe amily co-
ecep o s equi e he adap o p o eins TRAF (TNFR-associa ed
ac o ), namely TRAF2 and TRAF5, o link o downs eam sig-
naling media o s (Table 1). He e, based on hei speci ic oles
in γδ T-cells, we shall discuss CD28 (o he Ig supe amily)
and he TNFR supe amily membe s, CD27, CD30, and CD137
(4-1BB).
The bes s udied cos imula o y ecep o , CD28, has his o ically
yielded pa adoxical esul s on γδ T-cells (46). We ha e ecen ly
eadd essed his issue o bo h human and mouse γδ T-cells. We
desc ibed ha CD28 is cons i u i ely exp essed on lymphoid γδ T-
cells and p omo es su i al and p oli e a ion ia IL-2 p oduc ion.
CD28 ecep o agonis s enhanced γδ T-cell expansion, which was
con e sely inhibi ed by blocking an ibodies agains i s B7 ligands
(42). Impo an ly, CD28-de icien mice displayed lowe ( ela i e
o con ols) numbe s o o al o ac i a ed γδ T-cells upon Plasmod-
ium be ghei in ec ion, and ailed o expand bo h hei IFN-γ+and
IL-17+subse s (42). In con as , Hayes and colleagues epo ed
ha bo h unc ional γδ T-cell subse s di e en ia ed and expanded
no mally in a Lis e ia model (80). I would be in e es ing o de e -
mine how a iable is he dependence on CD28 cos imula ion o
γδ T-cell esponses o dis inc in ec ious agen s.
In naï e mice, while CD28 is no equi ed o he de elopmen
o ei he IFN-γ+o IL-17+γδ T-cell subse s (80), he TNFR supe -
amily membe CD27 is selec i ely implica ed in he gene a ion o
IFN-γ+γδ T-cells (10). In ac , we showed ha CD27 exp es-
sion seg ega es IFN-γ+(CD27+) and IL-17+(CD27−)γδ T-cells.
Mos in e es ingly, hese pheno ypes a e es ablished in he hymus,
and since emb yonic s ages. Based on he esul s om ou (10) and
Chien’s (9) eams, he de elopmen o IFN-γ-p oducing γδ T-cells
seemingly equi es s ong TCR signaling and CD27 cos imula ion
in he hymus.
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Ribei o e al. Recep o signaling in γδ T-cells
Table 1 | Co- ecep o s o γδT-cells – ex acellula ligands and in acellula signaling pa hways.
Recep o Ligands In acellula signaling
ini ia o s/adap o s
Downs eam signaling
pa hway
Ta ge molecules Re e ence
CD28 B7.1 (CD80)
B7.2 (CD86)
PI3K
ITK
G b2
PI3K/AKT
G b2/MEK/ERK
IL-2, NF-κB, AP-1, Bcl-xL,
NFAT
(42–45)
CD27 CD70 TRAF2
TRAF5
Si a
IKK/NF-κB
JNK
NF-kB, Ca2+,cyclinD2,
Bcl2a1, Bcl-xL
(46–49)
CD30 CD30L TRAF2
TRAF5
TRAF/IKK/IkB
Ca2+
NF-κB, IL-4, IFNγ, IL-8, CC
chemokines
(46,50,51)
4-1BB
(CD137)
CD137L TRAF2 NF-κB, IFNγ(52–54)
IL-2R
IL-15R
IL-2
IL-15
Jak1
Jak3
PI3K/AKT
Jak/STAT4/STAT5
MEK/ERK
STAT1
IFNγ, TNF-α, T-be ,
eomesode min
(55–58)
IL-7R IL-7 Jak1
Jak3
STAT3 IL-17, SOCS3 (59)
IL-21R IL-21 Jak1
Jak3
STAT3 CXCL13,
CXCR5
(60)
NKG2D MIC(A–B) DAP10 PI3K/AKT NF-κB, RelB, Bcl-xL, Bcl-2 (32,46,61–63)
ULBP (1–6) G b2/VAV1/SOS1
H60 PKCθ/Ca2+
MULT1
RAE1
NKp30 B7-H6
BAT3
CD3ζcAMP/PKA CC chemokines: CCL3,
CCL4, CCL5
(64–67)
NKp44 NKp44L DAP12 Zap70/Syk (64,68–70)
DNAM-1
(CD226)
Nec in-like-5
Nec in-2
PKC
LFA-1
Fyn
SLP-76/VAV1/ERK (71,72)
PD-1 PD-L1 (B7-H1)
PD-L2 (B7-DC)
SHP-1
SHP-2
CK2/PTEN/PI3K/AKT
MEK/ERK
GSK-3, Bcl-xLSmad3,
Cdc25A, IFNγ, IL-2
(73–76)
BTLA HVEM SHP-1 Zap70/ERK IL-17, TNF, IL-2 (77–79)
SHP-2
Beyond i s ole in hymic di e en ia ion,CD27 is c i ical o he
expansion o pe iphe al IFN-γ-p oducing γδ T-cells upon in ec-
ion wi h he pes i uses o mala ia pa asi es in mice (81). We
showed ha , in he con ex o TCR s imula ion and upon liga-
ion o CD70, CD27 signaling ac i a es he non-canonical NF-κB
pa hway and enhances he exp ession o an i-apop o ic and cell
cycle- ela ed genes, hus p omo ing mu ine γδ T-cell su i al and
p oli e a ion (81).
We ha e also add essed he impac o CD27 cos imula ion
on he ac i a ion o human γδ T-cells. Adminis a ion o solu-
ble ecombinan CD70 enhanced, whe eas an i-CD27 (o an i-
CD70) an ibodies educed,Vγ9Vδ2 T-cell expansion in i o (82).
Mo eo e , CD27 signals induced calcium luxes and up egula ed
he exp ession o Cyclin D2 and he an i-apop o ic gene Bcl2a1.
Gi en he ypical IFN-γsec e ion and cy o oxici y o ac i a ed
Vγ9Vδ2 T-cells (30), ou wo k sugges s ha he modula ion
o CD70–CD27 signals may be bene icial in he con ex o γδ
T-cell-based cance immuno he apy.
Upon ac i a ion, human γδ T-cells can also exp ess ano he
TNFR supe amily membe , CD30 (83). CD30 signaling, which
po en ia ed calcium luxes induced by TCR ac i a ion, also
enhanced p o-in lamma o y cy okine p oduc ion (50). Recen ly,
Yoshikai and colleagues compa ed γδ T-cell homeos asis and
esponse o Lis e ia monocy ogenes in CD30-su icien e sus
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Ribei o e al. Recep o signaling in γδ T-cells
de icien mice. They demons a ed a selec i e deple ion o IL-17-
p oducing Vγ6+T-cells in mucosal issues in he s eady-s a e and
upon in ec ion (84). This associa ed wi h educed bac e ial clea -
ance, which could be escued, alongside he IL-17+Vγ6+T-cell
pool,by agonis ic an i-CD30 an ibody adminis a ion. In con as ,
Lee e al. epo ed ha agonis ic an i-CD137 (4-1BB) an ibodies
p omo ed he expansion o IFN-γ+Vγ1+T-cells, which p o ec ed
(in an IFN-γ-dependen manne ) also om Lis e ia in ec ion (52).
This s udy also showed ha 4-1BB was exp essed and unc ional
on ac i a ed human γδ T-cells, and i s liga ion upon cell ans e
p o ec ed NOD/SCID mice agains Lis e ia in ec ion.
In e es ingly, ac i a ed Vγ9Vδ2 T-cells also exp ess high le els
o 4-1BBL (CD137L) (85), which besides ac ing as a ligand o
4-1BB on T and NK-cells, may also pa icipa e in Vγ9Vδ2 T-cell
ac i a ion due o i s known e e se signaling abili y (86). This
may, in ac , also apply o CD70 (CD27-ligand), which is highly
induced upon phosphoan igen-media ed s imula ion o Vγ9Vδ2
T-cells (82,87). These possibili ies dese e u he in es iga ion.
SIGNAL 3: CYTOKINE RECEPTORS
In e leukins a e key de e minan s o T-cell su i al, p oli e a ion,
and di e en ia ion. IL-7, IL-15, and IL-2 a e essen ial o lym-
phocy e de elopmen and homeos asis; upon in lamma ion,o he
cy okines, namely, IL-1β, IL-12, IL-18, IL-21, and IL-23, ake a
cen al ole in de e mining T-cell unc ions. He e, we e iew he
main con ibu ions o homeos a ic and in lamma o y cy okines
speci ically o γδ T-cell physiology.
IL-7 and IL-15 a e seemingly he key de e minan s o mu ine γδ
T-cell de elopmen (88–90) and homeos asis (91). A ecen s udy
ha deple ed IL-7 speci ically om (Foxn1+) hymic epi helial
cells showed ha γδ T-cells we e signi ican ly educed in he adul
hymus and in he gu , whe eas hey we e comple ely absen in he
e al hymus and epide mis (89). In he de mis,i was also IL-7,bu
no IL-15, ha suppo ed he de elopmen and su i al o he es-
iden γδ T-cell popula ion (92). Con e sely, in he gu ,IL-15 seems
o play he p imo dial ole in sus aining he local in aepi helial
γδ T-cell compa men (93).
Unexpec edly, IL-7 was ecen ly epo ed o p omo e he
selec i e expansion o mu ine IL-17-p oducing γδ T-cells (59).
STAT3-dependen IL-7 signals allowed CD27−γδ T-cells o esis
ac i a ion-induced cell dea h (AICD) and unde go p oli e a i e
esponses o TCR agonis s. Such an IL-7/IL-17 axis was also
epo ed o be equi ed o he γδ T-cell esponse o i al hepa i is
in ec ion in i o (94). Mo eo e , IL-7 also seems o suppo he
expansion o human IL-17-p oducing γδ T-cells (59).
We ecen ly assessed he unc ional di e en ia ion o human
γδ hymocy es, which a e >80% o he Vδ1 sub ype. We obse ed
ha IL-15 and IL-2, bu no IL-7, induced he cy o oxic ype 1
(IFN-γ-p oducing) p og am in unc ionally imma u e γδ hymo-
cy es (55). This was consis en wi h p e ious da a on pe iphe al
γδ T-cells isola ed om cance pa ien s (95). Howe e , addi ional
epo s on pe iphe al Vγ9Vδ2 T-cell cul u es showed ha IL-15
o IL-2 s imula ion, despi e e icien ERK and AKT ac i a ion,
we e no su icien o induce e ec o esponses; hese equi ed
phosphoan igen-dependen TCR ac i a ion and downs eam cal-
cium mobiliza ion (56,96). Unexpec edly, in ou cul u es o γδ
(mos ly Vδ1) hymocy es, TCR s imula ion was no equi ed o
nei he ERK ac i a ion no T-be and eomesode min induc ion
and he acquisi ion o e ec o unc ions (55).
IL-2 and IL-15 play key oles in he pe iphe al expansion o
Vγ9Vδ2 T-cells in esponse o mic obial phosphoan igens o syn-
he ic d ugs like bisphosphona es (56,97). This no wi hs anding,
i is impo an o no e, owa d he he apeu ic applica ion o
Vγ9Vδ2 T-cells, ha op imal e ec o esponses seemingly equi e
he combina ion o hese cy okines wi h TCR agonis s. Thus,
ecen wo k om Chen and colleagues demons a ed ha he di -
e en ia ion o cy o oxic ype 1 Vγ9Vδ2 T-cells capable o con ol-
ling Mycobac e ium ube culosis in ec ion in macaques equi ed a
phosphoan igen/IL-2 combina ion (98).
E ec o γδ T-cell di e en ia ion is also g ea ly impac ed by
in lamma o y cy okines, pa icula ly IL-12 and IL-18 ha ypi-
cally p omo e IFN-γp oduc ion; and IL-1βand IL-23 ha mos ly
d i e IL-17 p oduc ion.
High exp ession o IL-12Rβexp ession on ac i a ed mu ine γδ
T-cells gua an ees a dominance o ype 1 (IFN-γ+) o e ype 2
(IL-4+) e ec o a es (99). Type 1 di e en ia ion is also p edom-
inan in human γδ T-cells, and can be u he enhanced by IL-18
(100,101) o IL-21 (102). The induc ion o a ype 17 p og am in
human γδ T-cells equi es pe sis en s imula ion wi h IL-23 o
neona al Vγ9Vδ2 T-cells (15); and IL-23 and IL-1βin he p es-
ence o TGF-β o adul Vγ9Vδ2 T-cells (13,103). In mice, IL-1β
and IL-23 a e also he main d i e s o abundan IL-17 p oduc-
ion by pe iphe al γδ T-cells (3,5,81,104–106), al hough ecen
da a su p isingly sugges ha IL-18 can eplace IL-1βin combin-
ing wi h IL-23 o induce IL-17 exp ession (107). In con as , IL-1β
ups eam o IL-1R seems essen ial o GM-CSF p oduc ion by γδ
T-cells (108).
Finally, IL-21 was ecen ly sugges ed o endow human Vγ9Vδ2
T-cells wi h B-cell helpe ac i i y associa ed wi h a T ollicula
helpe cell-like pheno ype (60,109), which may impac on he
gene a ion o high a ini y an ibodies agains mic obial in ec ions.
SIGNAL 4: NATURAL KILLER RECEPTORS
An impo an key cha ac e is ic ha allows he ecogni ion o
ans o med cells by γδ T-cells is he exp ession o a wide se o
ge mline-encoded ecep o s ha we e ini ially desc ibed in NK-
cells and hence a e collec i ely known as NK ecep o s (NKRs),
including na u al cy o oxici y ecep o s (NCRs).
The C- ype lec in-like NK ecep o g oup 2 membe D
(NKG2D) is he bes s udied NKR in γδ T-cells. NKG2D binds
ex acellula ly o mul iple ligands o he MIC(A–B) and ULBP
(1–6) amilies in humans; and o H60, MULT1, and a ious RAE1
molecules in mice (110). NKG2D ligands a e induced upon cellu-
la s ess, o example, downs eam o he DNA-damage esponse
pa hway in umo cells (111,112). The biological signi icance o
his ecogni ion sys em is unde lined by he inc eased suscep ibil-
i y o NKG2D-de icien mice o umo de elopmen (113).
In acellula ly, NKG2D binds o DNAX-ac i a ing p o ein o
10 kDa (DAP10), which ca ies an YXNM mo i ha a e y osine
phospho yla ion ec ui s PI3K o a G b2–Va 1–SOS1 signaling
complex (Table 1). This mo i is simila o ha in CD28, and
hus, NKG2D/DAP10 may p o ide T-cells wi h cos imula o y sig-
nals ha syne gize wi h he ITAM-based TCR/CD3 complex (61).
Howe e , unlike αβ T-cells bu simila ly o NK-cells, γδ T-cells can
F on ie s in Immunology |T Cell Biology Janua y 2015 | Volume 6 | A icle 15 | 4
Ribei o e al. Recep o signaling in γδ T-cells
exp ess bo h DAP10 and DAP12 (62). The la e con ains an ITAM
mo i , which a e y osine phospho yla ion ec ui s and ac i a es
Syk and ZAP70. In e es ingly, only mu ine bu no human NKG2D
is able o associa e wi h DAP12 (in addi ion o DAP10).
The con o e sy on a p ima y s imula o y e sus cos imula o y
ole o NKG2D in γδ T-cells has been discussed elsewhe e(46,114).
B ie ly, he cos imula o y unc ion o NKG2D in human Vγ9Vδ2
T-cells was suppo ed by addi i e e ec s on TCR-media ed ac i a-
ion:an up egula ion o cy okinep oduc ionuponMICA-NKG2D
in e ac ions (115); and an inc ease in in acellula calcium mobi-
liza ion and cy o oxic ac i i y (32). Howe e , o he lines o e i-
dence ha e sugges ed ha NKG2D signals can ac i a e γδ T-cells in
he absence o TCR engagemen : NKG2D liga ion can up egula e
CD69 exp ession in Vγ9Vδ2 T-cells o simila ex en as TCR s im-
ula ion (116); NKG2D bu no TCR blockade can inhibi Vγ9Vδ2
T-cell cy o oxici y agains a ious hema ological umo s (117);
and mu ine DETC can a ge umo s upon ecogni ion o NKG2D
ligands (6,118).
Ano he NKR implica ed in umo cell ecogni ion by Vγ9Vδ2
T-cells is DNAX accesso y molecule-1 (DNAM-1). DNAM-1 is
an Ig-like amily glycop o ein composed o a cy oplasmic domain
con aining h ee pu a i e si es o phospho yla ion by in acellu-
la kinases. The phospho yla ion o he Se 329 by p o ein kinase
C (PKC) was shown o be c i ical o he associa ion be ween
DNAM-1 and LFA-1, which ec ui s he Fyn S c kinase o phos-
pho yla e he Ty 322 o DNAM-1, hus ini ia ing downs eam
signaling leading o SLP-76 and Va 1 phospho yla ion (Table 1)
(119). An ibody-media ed DNAM-1 blockade impai ed Vγ9Vδ2
T-cell cy o oxici y and IFN-γp oduc ion agains hepa ocellula
ca cinoma lines exp essing Nec in-like-5 (71).
Recen ly, we cha ac e ized a Vδ1+T-cell popula ion capable o
a ge ing hema ological umo s esis an o ully ac i a edVγ9Vδ2
T-cells (120). Unexpec edly, he enhanced kille unc ion esul ed
om induced NCR exp ession, namely NKp30 and NKp44, which
had been p e iously ega ded as NK-speci ic ma ke s. Al hough
nei he Vδ1+no Vδ2+cells exp ess NCRs cons i u i ely, hese can
be up egula ed selec i ely in Vδ1+cells by PI3K/AKT-dependen
signals p o ided by γc cy okines (IL-2 o IL-15) and TCR s imu-
la ion. Once exp essed on he cell su ace, NKp30 and NKp44 can
signal ia CD3ζand DAP12, espec i ely (64). We u he showed
ha NKp30 and NKp44 a e bo h unc ional in NCR+Vδ1+T-
cells and syne gize wi h NKG2D o a ge lymphocy ic leukemia
cells (120).
In sum, NKRs seem c i ical o umo ecogni ion and
deploymen o he cy o oxic p og am ha is endowed by
TCR/γc cy okine-dependen di e en ia ion, hus de ining dis-
inc mechanisms o be in eg a ed in γδ T-cell-media ed cance
immuno he apy.
SIGNAL 5: INHIBITORY RECEPTORS
Beyond e icien ac i a ion and deploymen o e ec o unc ions,
i is necessa y o nega i ely egula e he T-cell esponse in o de o
e u n o he homeos a ic baseline. Inhibi o y ecep o s like PD-1
o CTLA-4 a e known o be c i ical o his con ac ing phase o he
T-cell esponse and ha e become majo clinical a ge s in cance
immuno he apy. Al hough γδ T-cells a ely exp ess CTLA-4, hey
can up egula e PD-1 upon ac i a ion, while hey cons i u i ely
exp ess BTLA, and hus hese wo ecep o s may be he key o
con ol γδ T-cell esponses.
P og amed dea h-1 (PD-1) is absen o low exp essed on ci cu-
la ingVγ9Vδ2 T-cells bu is apidly induced upon ac i a ion (121).
The cy oplasmic ail o PD-1 con ains conse ed immuno ecep o
y osine-based inhibi o y mo i (ITIM) and swi ch mo i (ITSM),
bo h o which a e phospho yla ed o ec ui nega i e egula o s
ha block Lck ac i i y downs eam o he TCR complex (122).
Mo eo e , PD-1 liga ion can augmen he ac i i y o he p o ein
phospha ase and ensin homolog (PTEN), a cellula phospha ase
ha inhibi s PI3K/AKT signaling and hus leads o impai ed su -
i al, p oli e a ion, and IL-2 elease (123). The exp ession o he
ligand PD-L1 on umo cells inhibi ed Vγ9Vδ2 T-cell cy o oxic-
i y and IFN-γp oduc ion (121). Howe e , zoled ona e-induced
accumula ion o P-Ags in umo cells and consequen Vγ9Vδ2
TCR ac i a ion seemed o o e come he inhibi o y e ec o PD-
1/PD-L1 in e ac ions. Mo e esea ch is equi ed o unde s and
he ull ex en o wha PD-1 may con ol γδ T-cell unc ions and
homeos asis.
B- and T-lymphocy e a enua o (BTLA) is ano he inhibi o y
ecep o , membe o he CD28 amily and s uc u ally ela ed o
PD-1 and CTLA-4. Binding o i s ligand, he pes i us en y medi-
a o (HVEM), induces phospho yla ion o he ITIM domain and
associa ion wi h SH2 domain-con aining p o ein y osine phos-
pha ase 1 (SHP-1) and SHP-2, which leads o a enua ion o cel-
lula ac i a ion and g ow h (124). Recen da a showed ha BTLA
engagemen wi h HVEM educed P-Ag/TCR-media ed signaling
and inhibi ed Vγ9Vδ2 T-cell p oli e a ion, including in esponse
o lymphoma cells (77). Con e sely, BTLA-HVEM blockade using
monoclonal an ibodies enhanced Vγ9Vδ2 TCR signaling and may
hus ha e he apeu ic po en ial o he posi i e manipula ion o
γδ T-cells.
A de ailed s udy on BTLA unc ion in mu ine γδ T-cells has
e ealed a selec i e in ol emen in he homeos asis o he IL-
17-p oducing CD27−γδ T-cell subse (78). Al hough hese cells
cons i u i ely exp ess low le els o BTLA, i is up egula ed by IL-7
s imula ion and he eby limi s γδ T-cell numbe s. Consequen ly,
BTLA-de icien mice accumula ed IL-17+CD27−γδ T-cells and
we e mo e suscep ible ( han wild- ype con ols) o de ma i is,
which could be e e sed by agonis BTLA an ibodies. Thus, BTLA
may be an impo an a ge o con olling pa hogenic γδ T-cells
in in lamma o y and au oimmune diseases.
CONCLUDING REMARKS
A mul i ude o su ace ecep o s has been shown o pa icipa e
in γδ T-cell di e en ia ion and ac i a ion. Howe e , some c u-
cial aspec s emain o be elucida ed, such as he iden i y o mos
γδTCR ligands. Mos impo an ly, we mus imp o e he ans e
o pas and cu en basic esea ch in o u u e p o ocols o γδ T-
cell-basedimmuno he apy. In hiscon ex ,some keyques ionsa e:
how o balance γδTCR ac i a ion wi h“exhaus ion”due o ch onic
s imula ion? Wha can be achie ed by manipula ing he NK-like
ac i a ion mode o γδ T-cells? Which cos imula o y ecep o s
should be modula ed, and a wha s ages, o boos he desi ed γδ
T-cell esponses? Which combina ions o cy okines enable he bes
e ec o γδ T-cells o each he apeu ic applica ion? Which ecep-
o s a e mos use ul o une down o swi ch o pa hogenic e ec o
www. on ie sin.o g Janua y 2015 | Volume 6 | A icle 15 | 5
Ribei o e al. Recep o signaling in γδ T-cells
γδ T-cells? The answe s o hese ques ions mus be ob ained in
app op ia e in i o p e-clinical models and hope ully nex in he
clinic.
Fo now, we would like o p opose ha he i e ypes o ecep-
o signals e iewed he e de ine i e dis inc laye s o egula ion
o γδ T-cell di e en ia ion, ac i a ion, and unc ion. The γδTCR
is c i ical o he ini ial s ages o di e en ia ion and o p oli e a-
i e esponses; bo h p ocesses u he equi e cy okine signals ha
p omo e cell su i al, p oli e a ion, and e minal e ec o unc-
ion. Cos imula o y and inhibi o y ecep o s con ol he ex en o
γδ T-cell expansion, wi h in e es ing biases owa d speci ic e ec-
o subse s. Finally, NK ecep o s play a decisi e ole in umo cell
a ge ing by γδ T-cells. Thus, we belie e ha he ecogni ion o
“s essed sel ” can be media ed by he γδTCR bu also chie ly by
NK ecep o s like NKG2D. As such, he cha ac e iza ion o bo h
ype o ligands on umo s may be c i ical o design p o ocols,selec
and moni o pa ien s, and inc ease he chances o e icacious γδ
T-cell-based cance immuno he apies.
ACKNOWLEDGMENTS
We hank Daniel Co eia o help ul discussions on hese
opics. Ou wo k is suppo ed by Fundação pa a a Ciên-
cia e Tecnologia (SFRH/BD/84123/2012 o Sé gio T. Ribei o;
SFRH/BPD/78135/2011 and EXPL/IMI-IMU/0170/2013 o Julie
C. Ribo ) and Eu opean Resea ch Council (S G_260352 o B uno
Sil a-San os).
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Con lic o In e es S a emen : B uno Sil a-San os is a co- ounde and sha e holde
o LymphAc S.A. The o he co-au ho s decla e ha he esea ch was conduc ed in
he absence o any comme cial o inancial ela ionships ha could be cons ued as
a po en ial con lic o in e es .
Recei ed: 21 Oc obe 2014; accep ed: 08 Janua y 2015; published online: 26 Janua y
2015.
Ci a ion: Ribei o ST, Ribo JC and Sil a-San os B (2015) Fi e laye s o ecep o
signaling in γ δ T-cell di e en ia ion and ac i a ion. F on . Immunol. 6:15. doi:
10.3389/ immu.2015.00015
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www. on ie sin.o g Janua y 2015 | Volume 6 | A icle 15 | 9
