REVIEW
published: 18 Decembe 2018
doi: 10.3389/ immu.2018.02994
F on ie s in Immunology | www. on ie sin.o g 1Decembe 2018 | Volume 9 | A icle 2994
Edi ed by:
Be na d Malissen,
INSERM U1104 Cen e
d’Immunologie de Ma seille-Luminy,
F ance
Re iewed by:
Renaud Lesou ne,
INSERM U1043 Cen e de
Physiopa hologie de Toulouse Pu pan,
F ance
Jacques A. Nunes,
INSERM U1068 Cen e de Reche che
en Cancé ologie de Ma seille, F ance
*Co espondence:
Alexand e M. Ca mo
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
T Cell Biology,
a sec ion o he jou nal
F on ie s in Immunology
Recei ed: 31 July 2018
Accep ed: 04 Decembe 2018
Published: 18 Decembe 2018
Ci a ion:
Gonçal es CM, Hen iques SN,
San os RF and Ca mo AM (2018)
CD6, a Rheos a -Type Signalosome
Tha Tunes T Cell Ac i a ion.
F on . Immunol. 9:2994.
doi: 10.3389/ immu.2018.02994
CD6, a Rheos a -Type Signalosome
Tha Tunes T Cell Ac i a ion
Ca ine M. Gonçal es1,2, Sónia N. Hen iques1,2,3, Ri a F. San os1,2,3 and
Alexand e M. Ca mo1,2*
1Ins i u o de In es igação e Ino ação em Saúde, Uni e sidade do Po o, Po o, Po ugal, 2Ins i u o de Biologia Molecula e
Celula , Po o, Po ugal, 3Ins i u o de Ciências Biomédicas Abel Salaza and Faculdade de Ciências, Uni e sidade do Po o,
Po o, Po ugal
Following T cell ecep o igge ing, T cell ac i a ion is ini ia ed and ampli ied by he
assembly a he TCR/CD3 mac ocomplex o a mul i ude o s imula o y enzymes ha
ac i a e se e al signaling cascades. The po ency o signaling is, howe e , modula ed by
a ious inhibi o y componen s al eady a he onse o ac i a ion, long be o e co-inhibi o y
immune checkpoin s a e exp essed o help e mina ing he esponse. CD5 and CD6 a e
su ace glycop o eins o T cells ha ha e de e minan oles in hymocy e de elopmen ,
T cell ac i a ion and immune esponses. They belong o he supe amily o sca enge
ecep o cys eine- ich (SRCR) glycop o eins bu whe eas he inhibi o y ole o CD5
has been es ablished o long, he e is s ill con o e sy on whe he CD6 may ha e
simila o an agonis ic unc ions on T cell signaling. Analysis o he s uc u e and
molecula associa ions o CD5 and CD6 indica es ha hese molecules assemble a
he cy oplasmic ail a conside able numbe o signaling e ec o s ha can pu a i ely
ansduce di e se ypes o in acellula signals. Biochemical s udies ha e concluded ha
bo h ecep o s can an agonize he low o TCR-media ed signaling; howe e , he impac
ha CD5 and CD6 ha e on T cell de elopmen and T cell-media ed immune esponses
may be di e en . He e we analyze he signaling unc ion o CD6, he common and also
he di e en p ope ies i exhibi s compa ing wi h CD5, and in e p e he unc ional e ec s
displayed by CD6 in ecen animal models.
Keywo ds: inhibi o y ecep o s, CD5, CD6, signalosome, T lymphocy es
INTRODUCTION
An igen-speci ic T cell ac i a ion is igge ed by he T cell ecep o (TCR) ecogni ion o a
cogna e pep ide p esen ed by an igen p esen ing cells (APC), bu i is o e all con olled by a
ple ho a o o he cell su ace ecep o s ha ei he inc ease o ep ess he s eng h o he signals,
he combina ion o which de e mines he ou come o T cell-media ed esponses. Mos o he
ecep o s do no con ain in insic enzyma ic ac i i ies so hei unc ion elies on he es ablishmen
o in e ac ions wi h signaling e ec o s, and also on an app op ia e localiza ion whe e hey can exe
hei ole, de e mined ex acellula ly by he binding o speci ic ligands exp essed on he APC and
in acellula ly h ough connec ing wi h he cy oskele on.
Inhibi o y co- ecep o s, such as he immune checkpoin s P og ammed cell dea h p o ein 1
(PD-1), Cy o oxic T-lymphocy e-associa ed p o ein 4 (CTLA4), T cell immuno ecep o wi h Ig
and ITIM domains (TIGIT), Lymphocy e-ac i a ion gene 3 (LAG-3), and B- and T-lymphocy e
a enua o (BTLA) a e c ucial o hal he p og ession o o e mina e cell ac i a ion once hey
become exp essed, gi en ha hey a e s ongly induced upon ac i a ion (1–5). They exe hei
Gonçal es e al. CD6 Tunes T Cell Ac i a ion
inhibi o y e ec in acellula ly h ough e y limi ed and de ined
in e ac ions u ilizing ITIM, ITSF, o o he sequences o hei
cy oplasmic ails ha a e bound by inhibi o y enzymes, ypically
se ine/ h eonine o y osine phospha ases (6–10). Mo eo e ,
some o hese inhibi o y co- ecep o s also in e e e wi h co-
s imula o y ecep o s h ough ex acellula compe i ion o he
same ligands (11–14).
A di e en class o inhibi o y ecep o s ha can be ac i e
immedia ely ollowing he igge ing o he TCR and hus
modula e T cell signaling a he onse o ac i a ion is exempli ied
by CD5: cons i u i ely exp essed on nea ly all T cell subse s,
including naï e and non-ac i a ed cells (15,16), and loosely
in e ac ing wi h he TCR/CD3 complex (17), CD5 is able o
modula e esponses concomi an ly wi h TCR igge ing (18,
19). The exp ession o CD5 can inc ease signi ican ly upon
hymocy e and ma u e T cell ac i a ion such ha he po ency
o he inhibi ion is p opo ionally adjus ed in acco dance o he
a ini y o TCR ecogni ion o pep ide/MHC and TCR-dependen
signaling in ensi y (20,21). This indica es ha he a iable le els
o CD5 exp ession a e impo an o coun e ac he s eng h o
TCR signaling (22).
CD6 sha es wi h CD5 many gene ic, s uc u al, and unc ional
cha ac e is ics, among hem he capaci y o in e ac wi h he
TCR/CD3 complex, o be y osine-phospho yla ed and ac i a ed
upon TCR igge ing, and sligh ly inc eases i s su ace exp ession
upon T cell ac i a ion (23–26). Howe e , some di e ences
be ween he kine ics o exp ession o CD5 and CD6 du ing
hymocy e on ogeny and selec ion and T cell subse pola iza ion
as well as appa en di e en equi emen s o ligand binding
sugges ha CD5 and CD6 may ha e non-coinciden oles du ing
hymocy e de elopmen , T cell ac i a ion and immune esponses.
Ne e heless, in cellula sys ems i was also shown ha he
s eng h o ac i a ion co ela es in e sely wi h he exp ession
o CD6 (27). The e o e, simila ly o CD5 and dis inc i e om
he immune checkpoin s ha can shu down ac i a ion a la e
s ages, CD6 may be a heos a - ype egula o o ac i a ion, ine-
uning he esponse depending on he s eng h o he an igenic
challenge.
CD6 IS A HUB FOR THE ASSEMBLY OF
STIMULATORY AND INHIBITORY
EFFECTORS
A he ime o he cloning o hei genes and ini ial unc ional
cha ac e iza ion o he p o eins, CD5 and CD6 we e ega ded
as co-s imula o y ecep o s ha ampli ied TCR-dependen
ac i a ion (28–31). In he case o CD5, he unc ion o he
molecule was soon a e e ised ollowing he de elopmen o
mice wi h a dis up ed Cd5 gene (18). The lack o simila de ini i e
models add essing he ole o CD6 in i o un il e y ecen ly
delayed signi ican ly he p og ess on CD6 esea ch, and caused
ha he knowledge on he unc ion o CD6 is s ill lagging
conside ably behind.
The e a e many common aspec s in he biochemical
beha io o CD5 and CD6 and in ac hey can in e ac wi h
each o he in non-ac i a ed T cells (32,33). Upon an igen
ecogni ion and T cell-APC conjuga ion, bo h ecep o s localize
a he cen e o he immunological synapse (33). In con ac
wi h he TCR/CD3 signaling machine y, CD5 and CD6 a e
e y apidly phospho yla ed on y osine esidues (19,24),
p esumably by he SRC- amily kinase LCK, wi h he concomi an
docking o in acellula media o s ha con ain SH2 domains,
semi-au onomous conse ed s uc u al domains ha bind o
phospho yla ed y osine esidues. The ne con ibu ion o ei he
CD5 and CD6 appea s o be inhibi o y, gi en ha cells ha lack
any o he ecep o s a e signi ican ly mo e esponsi e o an igenic
o mi ogenic s imula ion (22,34). Howe e , he numbe and
di e si y o e ec o s ha associa e wi h CD5 and/o CD6,
depending o no on y osine phospho yla ion, would no gi e
an ob ious idea o he ep essi e po en ial o he ecep o s, gi en
ha many in e ac ing pa ne s a e e ec i ely p o ein y osine
kinases ha a e no mally associa ed wi h signaling p og ession.
These include LCK, FYN, ZAP70, and addi ionally in he case o
CD6, he TEC- amily kinase ITK (32,35–37).
Pe haps his agg ega ion o kinases a he cy oplasmic ail
o CD5 and CD6 explains he beha io obse ed in hei ini ial
cha ac e iza ion when ei he ecep o , when igge ed oge he
wi h he TCR/CD3 complex wi h monoclonal an ibodies,
ampli ied he ac i a ion signals o igina ed a he TCR complex.
No wi hs anding his possibly a i ac ual con ibu ion o
ac i a ion de e mined by he in i o expe imen al design, i is
also possible ha he kinases may ac ually con ibu e o posi i e
signaling ia CD5 and CD6 in e y de ined con ex s, hus
explaining he dual unc ion ha has been many imes a ibu ed
o CD6 and occasionally o CD5.
CD5 con ains ou y osine esidues on i s cy oplasmic
domain, ha when phospho yla ed cons i u e pu a i e si es o
he docking o SH2 domain-con aining cy oplasmic molecules.
Ty osine 402 is close o e en bu ied wi hin he plasma memb ane
and he e o e i is dispu able whe he i can ac ually be
phospho yla ed. None heless, he emaining y osine esidues o
CD5, when phospho yla ed, ha e been o a long ime shown o
bind o he y osine kinase LCK (35), he y osine phospha ase
SHP1 (38,39), he ubiqui in ligases CBL and CBLB (40,41),
he GTPase ac i a ing p o ein o RAS (RASGAP) (40) and he
lipid kinase PI3K (42), while he associa ions o CD5 wi h he
p o ein kinases FYN and ZAP70 ha e no been shown o be di ec
(Figu e 1A).
CD6 possesses possibly he longes cy oplasmic ail o he
known ecep o s o leukocy es, con aining amongs o he
signaling mo i s nine y osine esidues. Howe e , ewe han
expec ed in e ac ions o CD6 wi h SH2 domain-con aining
e ec o s ha e been epo ed o da e, possibly because esea ch
on CD6 unc ion has been pe o med less sys ema ically han
ha on CD5 (Figu e 1B). Mo eo e , mos o he disclosed
in e ac o s o CD6 seem o be mo e ela ed o ac i a ion
pa hways a he han o ep ession mechanisms, including
he y osine kinases LCK, FYN, ZAP70, and ITK ha we e
shown o be associa ed wi h CD6 bu no con i med o
be dependen on phospho y osine-SH2 domain binding.
Addi ionally, he adap o s SLP76 (27), TSAD (43), GADS,
and GRB2 (44), ha ha e es ablished oles in T cell ac i a ion
ha e been shown o bind o he wo mos ca boxyl- e minal
F on ie s in Immunology | www. on ie sin.o g 2Decembe 2018 | Volume 9 | A icle 2994
Gonçal es e al. CD6 Tunes T Cell Ac i a ion
FIGURE 1 | CD5 and CD6 a e hubs o he assembly o e ec o enzymes and adap o s—(A) CD5 binding pa ne s: CD5 con ains in i s cy oplasmic ail ou y osine
esidues, o which h ee (Y453, Y465, and Y487) a e belie ed o be phospho yla ed upon TCR igge ing and can bind he SH2 domains o LCK, RASGAP, CBL,
CBLB, SHP1, and PI3K. Rec ui men o CBL o he C- e minal egion o CD5 is impo an o he ubiqui yla ion and deg ada ion o se e al subs a es ollowing TCR
engagemen , including VAV. CK2 is also able o bind o he cy oplasmic ail o CD5 h ough o he mechanisms. The in e ac ion wi h FYN is also no dependen on
y osine phospho yla ion. CSK associa es wi h he CD5 signalosome possibly h ough he coope a ion wi h PAG, CBL, o CBLB. CD5 is ep esen ed in duplica e o
accommoda e all binding pa ne s; (B) CD6 binding pa ne s: CD6 con ains in i s cy oplasmic ail nine y osine esidues ha when phospho yla ed can dock he SH2
domains o SLP76, TSAD, GADS, GRB2, and SHP1. The in e ac ions wi h LCK, FYN, ZAP70, and ITK we e no shown o be dependen on SH2 domain binding o
phospho y osine esidues, bu ITK may be ec ui ed h ough i s associa ion wi h TSAD. CD6 binds h ough he C- e minal sequence o he PDZ domains o syn enin.
The CD6 signalosome is depic ed in he igh . S uc u es a e no d awn o scale.
phospho y osines o CD6. CD6 also binds o he sca olding
p o ein syn enin-1, bu he in e ac ion is likely media ed
by he andemly a anged PDZ domains o syn enin-1
(45).
In e es ingly, some o he pape s ha epo ed he
phosphop o ein-dependen molecula in e ac ions o CD6
desc ibed he coinciden inding ha he same molecules could
also dock on o he phospho y osine si es o Linke o ac i a ion
o T cells (LAT), a memb ane-bound adap o o he main axis o
he TCR-media ed pa hway. In an unbiased in i o p o eomics
sc eening, Roncagalli e al. desc ibed he LAT-independen
associa ion o SLP76 o CD6 (46), while Hem e al. showed ha
TSAD bound o bo h LAT and CD6 (43). Gi en ha addi ionally
GRB2 and GADS a e well-es ablished binde s o LAT (47), i
eme ges ha CD6 displays some cha ac e is ics o memb ane-
bound adap o s, such as LAT and Phosphop o ein associa ed
wi h glycosphingolipid-en iched mic odomains 1 (PAG) in ha
i con ains mul iple y osine esidues ha once phospho yla ed
can couple o a di e se se o signaling e ec o s, possibly eeding
on o a ious, con e gen o di e gen , signaling pa hways (48).
F on ie s in Immunology | www. on ie sin.o g 3Decembe 2018 | Volume 9 | A icle 2994
Gonçal es e al. CD6 Tunes T Cell Ac i a ion
The e o e, and much like LAT and PAG, CD6 seems o
cons i u e a signalosome ha assembles many di e en enzymes
and adap o s ha can impac on signal p opaga ion in di e en
pa hways and po en ially wi h di e gen ou comes. La knockou
mice, howe e , show a e y di e en beha io han hose de icien
o CD6 (desc ibed la e in his pape ), displaying a block in he
de elopmen o hymocy es a he double nega i e s age and a
comple e absence o ma u e T cells (49). This es ablished LAT
as a c ucial adap o o T cell signaling leading o lymphocy e
di e en ia ion and also o T cell ac i a ion. On he o he hand,
mice wi h a dis up ed Pag gene, much simila ly o Cd6-de icien
bu also o Cd5-de icien animals, ha e no o e all di e ences
in o al numbe s o T cells han wild- ype mice; and e ec o
T cells, al hough no naï e, a e mo e p one o ac i a ion upon
TCR a ge ing (50). PAG is essen ial o he phospho y osine-
dependen docking o he p o ein y osine kinase CSK, a majo
inhibi o y enzyme o T cell ac i a ion ha phospho yla es he
inhibi o y ca boxyl- e minal y osine esidues o LCK and FYN,
inac i a ing hese kinases (51,52). In e es ingly, CD5 seems o
be a ele an al e na i e docking ecep o o CSK, and in ac
PAG and CD5 may coope a e in he inhibi ion o FYN (36,41).
O e all, i appea s ha while LAT is a hub o he assembling o
posi i e e ec o s, CD5 as well as PAG can be iewed as inhibi o y
signalosomes. Whe he CD6 is an ac i a ing, inhibi o y, o mul i-
pu pose sca olding ansmemb ane ecep o is s ill unde deba e.
Gi en ha CD6, besides being s uc u ally e y simila o
CD5, sha es wi h i many ea u es, such as p o ile o exp ession
and unc ional oles in he biochemical ep ession o T cell
ac i a ion, i would be expec ed o a leas plausible ha , simila ly
o CD5, i could couple o analogous signaling inhibi o y
pa ne s. A ecen epo has in ac desc ibed he in e ac ion
o CD6 wi h he p o ein phospha ase SHP1 (26), cons i u ing
his he i s solid biochemical e idence ha CD6 can couple o
inhibi o y signaling.
CAN LIGAND BINDING AND SIGNALING
INHIBITION BE UNCOUPLED EVENTS?
Unlike PAG o LAT, CD6 con ains s uc u ed ec odomains ha
a e sui able o es ablish in e ac ions wi h ex acellula ligands.
CD6 binds o CD166, widely exp essed in many cell ypes
and issues (53,54). and ecen ly CD318 was iden i ied as an
al e na i e ligand in cells de i ed om human hymus, skin,
syno ium, and ca ilage (55,56). Howe e , he e is no absolu e
equi emen o CD6 o bind o ligands o be able o exe i s
inhibi o y unc ion (34). This is a cha ac e is ic common o CD5
(57). The e o e, hese wo ecep o s can be gene al a enua o s o
TCR-media ed signaling independen o any mechanical e ec s
o ligand binding o o any pa icula memb ane localiza ion. So,
i he e can be a unc ional uncoupling be ween hese wo ea u es
o he molecules, wha may be he ole o he ec odomains and he
consequences o binding o ligands?
Du ing hymocy e de elopmen , he exp ession o CD6
inc eases s eadily om double nega i e (DN) o double posi i e
(DP) and o single CD4+o CD8+ hymocy es, dec easing
hen sligh ly in he nega i ely selec ed single CD4+o CD8+
hymocy es jus be o e hymic emig a ion, and o ma u e T cells
(58). The inc easing exp ession o CD6 a o s he in e ac ion
wi h CD166, highly exp essed on hymic epi helium, possibly
p o iding an i-apop o ic signals and also inc easing he adhesion
o hymocy es o hymic epi helial cells. Howe e , his signal
uning- ela ed a ia ion o exp ession is a gene al cha ac e is ic
and no a di e en ia ion ea u e, i.e., hymocy es a e exposed
o APCs ha all exp ess he same pu a i e CD6 ligands and
hus he e should be no dis inc i e ou come in selec ion o
subse pola iza ion be ween di e en hymocy es based solely on
whe he o no CD6 binds o i s ligand.
The scena io can be ema kably di e en ega ding he
ac i a ion o ma u e T cells, hough. The in e ac ion be ween
CD6 and CD166 is one o he s onges be ween cell su ace
adhesion molecules, wi h a dissocia ion cons an (KD) o 0.4–
1.0 µM measu ed by su ace plasmon esonance (59), and
con ibu ing o binding be ween T cells and APC wi h o ces
equi alen o hose o in eg ins, as quan i ied by a omic o ce
mic oscopy (60). In eg a ing his in o ma ion wi h he inhibi o y
con ibu ion owa d signaling, i eme ges ha CD6 can possibly
ha e a dual ole, he i s o which is o p omo e cellula adhesion,
acili a ing he TCR scanning o speci ic pep ides. Upon an igen
ecogni ion and he o ma ion o immunological synapses, CD6
can hen adjus he s eng h o T cell ac i a ion h ough he
a enua ion o he signaling cascades. These ea u es a e also
gene ic conside ing T cell ac i a ion as a whole, gi en ha mos
APCs do exp ess he ligand CD166. Bu he ac is ha in di e en
con ex s wi h dis inc APCs, possibly exp essing a ied le els o
CD166 bu also a med wi h di e en se s o cos imula o y o
co-inhibi o y ligands o he many cell su ace ecep o s o T
cells, CD6 may impac di e en ly on he signaling pa hways and
can e en ually in luence on he pola iza ion o T cell subse s
and esponses, namely in he de elopmen o Th1 and Th17
sub-popula ions (61).
As o CD5, no APC-exp essed ligand has been demons a ed
so a ; howe e , i was ecen ly shown ha i can se e as an
al e na i e ecep o o IL-6, leading o he ac i a ion o he
ansc ip ion ac o STAT3 (62). Al hough his obse a ion was
made in B1a cells, i ne e heless opens he pe spec i e o IL-
6 being able o p omo e Th17 esponses when binding o T
cell-exp essed CD5.
THE MODULATORY ROLE OF CD6
DURING THYMOCYTE DEVELOPMENT
Two ecen epo s on independen Cd6 knockou models ha e
inally con i med ha a he cellula le el, he ne con ibu ion
o CD6 o signaling is gene ally inhibi o y (24,25). Isola ed
CD4+and CD8+T cells om he mu an mice displayed
signi ican ly augmen ed ac i a ion upon an i-CD3 igge ing
han cells isola ed om wild- ype mice (24,25), highligh ing he
inhibi o y ole o CD6 in T cell ac i a ion. I appea s, howe e ,
ha he s eng h o inhibi ion is milde han ha o CD5.
The gene a ion o Cd6 knockou mouse models has been
help ul in unde s anding he ole o he p o ein du ing hymocy e
selec ion. Al hough he equency and o al numbe s o mos
F on ie s in Immunology | www. on ie sin.o g 4Decembe 2018 | Volume 9 | A icle 2994
Gonçal es e al. CD6 Tunes T Cell Ac i a ion
cell popula ions in he pe iphe y a e iden ical compa ing wild-
ype and CD6−/−mice, in he hymus he e seems o be a
pa ial impai men in he ansi ion om double-posi i e o
single posi i e hymocy es (63). Namely, he e is an inc ease in
he pe cen age o DP hymocy es unde going selec ion, which is
accompanied by a dec ease o CD4+o CD8+SP hymocy es
ha comple e selec ion. Besides, he pe cen age o CD4+SP
hymocy es is educed in hese animals. The pe cen age o CD8+
SP cells is unal e ed bu a deepe look in o ha subpopula ion
e ealed ha , in Cd6 knockou mice, he pe cen age o CD8+
imma u e cells was inc eased while ha o CD8+ma u e cells was
dec eased (63). In summa y, CD6 is able o modula e signaling
du ing T cell de elopmen as he lack o he molecule changes
he h eshold o nega i e selec ion in he hymus esul ing in a
educed numbe o T cells ha ully ma u e (Figu e 2).
Simila s udies had been conduc ed o assess he ole o CD5
exp ession in de elopmen and how i a ec s he gene a ion o
ei he CD8+o CD4+T cell popula ions (18,64). Despi e he
ac ha he o e all e ec o CD5 exp ession in de elopmen
was ini ially disguised by he la ge epe oi e o exp essed TCRs
(65), he use o TCR- ansgenic mice allowed o unde s and
ha CD5 ac s as a nega i e egula o du ing T cell ma u a ion
(18,64). In ac , a subsequen s udy encompassing di e en TCR-
ansgenic animal models cla i ied ha he e ec o CD5 is ela ed
o i s le els o exp ession (22). In T cells wi h high-a ini y TCRs
(and consequen high exp ession o CD5), lack o CD5 ma kedly
dec eases posi i e selec ion, while inc easing nega i e selec ion.
In low-a ini y TCR-exp essing T cells, howe e , he loss o CD5
exp ession did no esul in such signi ican changes (22).
CD6 is also able o impac on he e iciency o T egs, a
pa icula subse o T cells esponsible o supp essing immune
esponses by inducing an igen ole ance. The abili y o T egs
o down egula e bo h e ec o and helpe T cells in esponse
o sel -an igens ende s hem impo an playe s in p e en ing
au oimmune diseases. T egs isola ed om he spleen o Cd6
knockou mice we e shown o be less e icien in supp essing
he p oli e a ion o con en ional T cells han hose ex ac ed
om wild- ype mice (63). Taking in o conside a ion he many
ea u es common o bo h CD6 and CD5, his obse a ion was
somewha su p ising, as he opposi e pheno ype had been seen
o Cd5 knockou mice (66). Speci ically, i was obse ed ha
T egs om Cd5 knockou mice we e mo e e icien in hei
supp essi e ac i i y han cells om wild- ype mice, consis en
wi h CD5 being a nega i e egula o (66). The explana ion o his
disc epancy may be ound in he global iew o he sys em: CD4+
T cells om he spleen o Cd5 knockou mice we e desc ibed
o exp ess sligh ly mo e CD6; on he o he hand, splenic CD4+
T cells om Cd6 knockou mice end o exp ess less CD5 (63).
The e o e, Cd5 knockou mice ul ima ely display T egs ha a e
mo e able o ep ess immune esponses whe eas Cd6 knockou
mice, exp essing less CD5 bu also less CD6, a e cha ac e ized
by less e icien T egs. This ansla es in o less supp ession o he
immune sys em. In summa y, when CD6 exp ession is inc eased
di ec ly o indi ec ly, he o e all esul seems o be a sys em mo e
equipped o one down immune esponses.
LIGAND BINDING IN THE PROMOTION OF
T CELL MIGRATION VS. SUBSET
POLARIZATION
Mice wi h dis up ed Cd6 genes display di e ing esponses in
he wo main in lamma o y disease se ings in es iga ed so a .
In he collagen-induced a h i is (CIA) model, Cd6 knockou
mice we e cha ac e ized by ea lie disease onse and inc eased
clinical sco e as well as wo sened hallma ks o he disease,
namely IL-6 and TNF exp ession in he join s (63), whe eas
in a model o mul iple scle osis, expe imen al au oimmune
encephalomyeli is (EAE), he absence o CD6 con e s esis ance
o he demyelina ing diso de (61). Al hough he mice s ains
we e di e en and no he con en ional usually used in he wo
di e en disease models, he dispa a e esponses could again
FIGURE 2 | CD6 a o s hymocy e di e en ia ion and ma u a ion and is equi ed o selec ion o hymocy es wi h high-a idi y TCRs. CD6 is exp essed a all s ages o
hymocy e de elopmen . I s exp ession is inc eased a he double posi i e s age in cells ha a e assigned o ma u a ion (CD69high). CD6 has an impo an ole limi ing
he h eshold o nega i e selec ion. The CD6-CD166 in e ac ion p omo es highe a ini y TCR-MHC-II/pep ide in e ac ions con ibu ing o CD4+selec ion. CD6−/−
mice ha e an inc eased equency o DP cells unde going selec ion. Con e sely, CD4+SP and CD8+SP ha e lowe numbe s o a e less ma u e, espec i ely. DN,
double nega i e hymocy es; DP, double posi i e hymocy es; CD4+SP, single posi i e CD4 hymocy es; TEC, hymic epi helial cells.
F on ie s in Immunology | www. on ie sin.o g 5Decembe 2018 | Volume 9 | A icle 2994

Gonçal es e al. CD6 Tunes T Cell Ac i a ion
poin o dual al e na i e oles o CD6 in T cell ac i a ion leading
o di e gen immune esponses. Howe e , when isola ed and
esponding in i o o an igenic o an ibody-induced ac i a ion,
CD6-nega i e cells we e mo e esponsi e in bo h cases (61,63).
This obse a ion again sugges s ha CD6 may ha e o he oles
han jus i s pa icipa ion in signal ansduc ion mechanisms.
Whe eas, in he CIA model he augmen ed eac i i y o
CD6−/−T cells is consis en wi h a cellula signaling inhibi o y
unc ion o CD6, o an inhibi o y CD6-media ed T cell esponse,
in EAE he absence o CD6 was sugges ed, a he , o impai T cell
mig a ion h ough b ain mic o ascula endo helial cells esul ing
in a lowe in il a e in he spinal co d o , among o he s, he
au o eac i e T cells. Al hough he expe imen s pe o med did
no add ess leukocy e ansmig a ion in i o bu ac ually used
b ain mic o ascula endo helial cells isola ed om wild- ype and
knockou mice (61), hese obse a ions a e conco dan wi h a
ecen epo whe e he e-enginee ed addi ional exp ession in
CD6 molecules o he domain (d3) ha in e ac s wi h CD166
signi ican ly p omo es T cell mig a ion in o he b ain in a b ain
cance model, whe e cance endo helium up egula es CD166
exp ession (67). On he whole, a plausible explana ion o he
di e gen impac o he lack o CD6 in he wo models is ha in
CIA, CD6neg cells a e mo e au o eac i e and in lic issue damage
whe eas in EAE he lowe T cell in il a ion in o he b ain is he
dominan e ec .
The hypo hesis ha he lowe EAE sco es in he absence o
CD6 a e due o less ansmig a ion is, howe e , in appa en
con adic ion wi h he in e p e a ion ha is gi en o he
CD6-dependen co esponding human pa hology: CD6 is a
suscep ibili y gene o mul iple scle osis (68), and indi iduals
ca ying a disease- ela ed polymo phism a he locus s17828933
wi hin he i s in on ha e inc eased le els o CD61d3 (69), a
na u ally occu ing CD6 iso o m ha lacks he CD166-binding
domain (70). Thus, in bo h mouse and human s udies, he
de ec i e T cells a e in disad an age o c oss he blood-b ain
ba ie ; bu whe eas in he mouse model he lack o cell
in il a ion is p o ec i e, in he human se ing, pa adoxically, he
condi ions a e se o induce o agg a a e he illness.
One main di e ence is ha in he mouse he whole molecule
is missing whe eas in humans he ull signaling po en ial is
p esen . Fu he mo e, cells ca ying he CD61d3 iso o m a e
mo e eac i e upon mAb challenge han cells exp essing wild-
ype CD6. How can all hese ea u es be econciled o explain he
p og ession and se e i y o he disease? Unless we conside ha
he mouse and human s udies a e oo di e en o be compa able,
he e is a p esen no simple answe o ha ques ion i only he
signaling aspec s o CD6 a e aken in o accoun . The e o e, a
possible unc ion o CD6 ha should be conside ed is in ac i s
impac on he pola iza ion o di e en T cell subse s in di e en
disease condi ions.
THERAPEUTIC CD6 MABS
Bughani e al. ha e de eloped an an i-mouse CD6 mAb,
mCD6D1, ha ecognizes he memb ane dis al domain o CD6
(d1), o amelio a e he incidence o EAE in C57BL/6 mice (26),
while Li e al. ha e used a mouse an i-human CD6-d1 mAb,
UMCD6, o e e se EAE p og ession in DBA/1 humanized mice
(61). I olizumab is a mouse mAb ha also binds o CD6-d1
(71) and ha has been ound o be e y e icien in ea ing
au oimmune pa hologies (72). Clinical ials o I olizumab ha e
been conduc ed o ea heuma oid a h i is and pso iasis,
yielding e y encou aging esul s (73,74). This an ibody has
al eady ecei ed app o al om he D ugs Con olle Gene al
o India as ea men o ch onic plaque pso iasis in 2013, wi h
ea ed pa ien s p esen ing less p oli e a i e T cells and dec eased
le els o p o-in lamma o y cy okines in he se um (75). Despi e
he posi i e ou comes ha a e eme ging om he use o his
an ibody, e y li le is known abou i s mechanism o ac ion and
how exac ly i impac s on T cell signaling (72).
UMCD6 and I olizumab ecognize o e lapping epi opes and
can pa ly inhibi he binding o soluble CD166 o T cell-
exp essed CD6, al hough subs an ially less han an i-CD6-d3
(76). The s uc u e o he CD6 ex acellula egion has only
ecen ly been sol ed (77), and i was specula ed ha an ibody
binding o CD6-d1 could pe haps hinde he abili y o CD6 o
in e ac wi h CD166 (26). Howe e , in di e en expe imen al
se ings he e ec o blocking o he di ec in e ac ion be ween
T cell exp essed-CD6 and APC-exp essed CD166 by an i-CD6d1
mAbs, o e en he educ ion o T cell-APC conjuga es, has
p oduced con adic o y esul s (70,71,78). Al hough i is
possible ha he p esence o massi e amoun s o an ibodies
deco a ing he su ace o T cells may ac ually educe he numbe
o T cell-APC conjuga es, ano he plausible explana ion is ha
he ac ion o he eagen s may ha e a di ec e ec on CD6-
media ed signaling, o al e na i ely on CD6-media ed T cell
pola iza ion. The i s case has been ex ensi ely documen ed
in i o and deli e s e y dispa a e esul s depending on he
mAb clone used and condi ions o cell cul u e and ac i a ion,
anging om signi ican ac i a ion o ma ked inhibi ion (79).
As o he second, he e is s ill insu icien documen a ion o
in i o s udies o allow o any conclusions o be wi hd awn
o he ime being; ne e heless, I olizumab has p o en e icacy
o ea human diseases ha a e cha ac e ized by ha ing Th17
pola iza ion and conco dan ly, in human PBMC cul u ed in
Th17 pola izing condi ions, addi ion o I olizumab seems o
dec ease he di e en ia ion o CD4+T cells in o he Th17 sub-se
and dec ease he p oduc ion o IL-17 (26).
CONCLUDING REMARKS
Al hough pe haps coun e in ui i ely a a i s glance,
signal inhibi ion elies hea ily on in acellula y osine
phospho yla ion. Mo eo e , he phospho yla ion o ac i a ion
and inhibi o y mo i s can be ca alyzed by exac ly he same
kinases and also be coinciden al in ime. The e o e, i canno
be unexpec ed ha T cell-exp essed inhibi o y ecep o s
unc ionally and physically associa e wi h kinases ha a e
known o be c ucial o T cell ac i a ion. CD6 associa es wi h
LCK, FYN, ZAP70, and ITK, p o ein y osine kinases ha a e
ega ded as componen s o signaling p og ession, and ye , his
complex molecule has been shown o bes ow T cells wi h a s ong
inhibi o y po en ial bo h in i o as well as in ex i o sys ems
(34,61,63).
F on ie s in Immunology | www. on ie sin.o g 6Decembe 2018 | Volume 9 | A icle 2994
Gonçal es e al. CD6 Tunes T Cell Ac i a ion
Howe e , a s aigh o wa d ca ego iza ion o CD6 as an
inhibi o , o al e na i ely, as a co-s imula o y ecep o , does
no su ice o explain he appa en di e si y o unc ions
ha he molecule displays in many di e en si ua ions. CD6
seems o exhibi many ea u es analogous o memb ane-
bound in acellula adap o s, such as LAT and PAG, as i
has mul iple y osine esidues on i s cy oplasmic domain
ha once phospho yla ed can couple o a ange o di e en
enzymes and adap o s, possibly eeding in o mul iple pa allel
signaling pa hways. Pe haps his can explain he an agonis ic
oles a ibu ed o he molecule in di e en expe imen al
se ups. On he o he hand, he ac ha CD6 es ablishes
obus ex acellula in e ac ions wi h APC-exp essed ligands
s ongly a o s he adhesion be ween T cells and APCs and
unequi ocally p omo es T cell ac i a ion. Whe he binding
o CD166 can, al e na i ely in di e en si ua ions, p omo e
T cell ac i a ion o ep ession, o impac on T cell subse
pola iza ion equi es u he in es iga ion. CD6 is being
ecognized as an impo an a ge o he apy agains se e al
au oimmune diseases and he use o he apeu ic CD6 mAbs
is s eadily inc easing. A majo challenge acing ahead is o
unde s and how hese eagen s can egula e CD6 unc ion o
be able o de ise he mos app op ia e ea men o human
disease.
AUTHOR CONTRIBUTIONS
CMG, SNH, RFS, and AMC w o e he manusc ip . CMG and
AMC designed he igu es.
ACKNOWLEDGMENTS
This wo k was inanced by FEDER-Fundo Eu opeu de
Desen ol imen o Regional unds h ough he COMPETE
2020-Ope acional P og amme o Compe i i eness and
In e na ionaliza ion (POCI), Po ugal 2020, and by
Po uguese unds h ough FCT-Fundação pa a a Ciência e a
Tecnologia/Minis é io da Ciência, Tecnologia e Ensino Supe io
in he amewo k o he p ojec POCI-01-0145-FEDER-032296
(PTDC/MED-IMU/32296/2017). Addi ional unds, including
unding o CMG, we e om he p ojec No e-01-0145-
FEDER-000012-S uc u ed p og am on bioenginee ed he apies
o in ec ious diseases and issue egene a ion, suppo ed by
No e Po ugal Regional Ope a ional P og amme (NORTE
2020), unde he PORTUGAL 2020 Pa ne ship Ag eemen ,
h ough he Eu opean Regional De elopmen Fund (FEDER).
SNH and RFS a e ecipien s o Ph.D. s uden ships om FCT,
e e ences SFRH/BD/133312/2017 and SFRH/BD/110691/2015,
espec i ely.
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