DOI: 10.1161/CIRCULATIONAHA.113.003261
Two Sides to Every Pro-Inflammatory Coin: New Insights into the Role of
Dendritic Cells in the Regulation of T-Cell Driven Autoimmune Myocarditis
Running title: Griffin et al.; Two sides to every pro-inflammatory coin
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Gabriel K. Griffin, MD; Andrew H. Lichtman, MD, PhD
Vasc
Va
scul
sc
ular
ul
a R
esearch Division, Dept of Path
hol
olog
ogy, Brigham and Wo
Wom
men’s Hospital and
Vascular
Research
Pathology,
Women’s
Har
Ha
rvard
rva
ard Medi
M
edi
dica
caal Sc
chooll, Bo
Bost
s on,
st
on, MA
Harvard
Medical
School,
Boston,
Add
Ad
dresss for
dres
for Correspondence:
Corres
Corr
espo
pond
nden
dence
ce::
Address
A
nddre H
cht
htman MD
PhD
D
Andrew
H. Li
Lichtman,
MD, Ph
Brigham and Women’s Hospital
77 Avenue Louis Pasteur, NRB-752P
Boston, MA 02115
Tel: 617-525-4335
Fax: 617-525-4329
E-mail: [email protected]
Journal Subject Code: Basic science research:[130] Animal models of human disease
Key words: myocarditis, nitric oxide, immunology, Editorial
1
DOI: 10.1161/CIRCULATIONAHA.113.003261
Myocarditis is a major cause of heart failure in young adults that is typically precipitated by
cardiac infection with organisms such as Coxsackie B virus or the parasite Trypanosoma Cruzi1.
Myocarditis has a variety of clinical presentations but is often characterized by severe ventricular
dysfunction and risk of fatal arrhythmia. Tissue injury during myocarditis is caused by direct
infection of cardiomyoctes and immune-mediated responses to microbial antigens; in addition,
autoimmune T cell and antibody responses to myocardial antigens can develop and persist even
after the inciting infection has been cleared. The autoimmune component of myocarditis
indicates a failure of self-tolerance mechanisms, and may be driven by molecular mimicry
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between microbial and myocardial self-antigens. Although there has been an emphasis on the
role
ole of autoantibodies in autoimmune myocarditis, such as those targeting the ȕ1
1 ad
adrenergic
dre
r ne
n rg
rgic
ic
receptor
eceptor or the Įmyosin heavy chain ĮMHC), this may reflect the relative ease of their
experimental
ex
xpe
peri
rim
ri
ment
ment
ntaal
al detection
det
ettec
ecti
tion as compared to assays off T cell
cell activationn by
by specific
sppec
ecific self-antigens.
Nonetheless,
N
onnetheless,
ne
tthe
he re
relevance
elev
ev
van
ncee ooff T ce
cells
ellls iiss ssupported
upppor
portedd bby
y the
he ffact
act th
tha
that
at llymphocytic
ymph
ym
p oc
ph
ocyt
ytic
yt
icc iinfiltrates
nffil
iltr
trat
tr
attess
including
ncl
clud
udin
ud
i g CD4
in
CD4+ hhelper
elpeer T cells
elpe
cell
llls can
can be
b demonstrated
dem
mon
onsttra
rate
teed in endocardial
end
ndoocar
nd
ocar
ardi
dial
al biopsy
bio
i psyy orr autopsy
aut
u op
opsy
sy sections
secti
ecti
t onns
taken
aken from ppatients
atie
at
ieentts wi
with
th
hm
myocarditis,
yoca
yo
caard
rdit
itis
is, an
is
andd by tthe
h fa
he
fact
act tthat
hatt ma
ha
many
ny ooff th
thee ca
car
cardiac
rdi
diac
ac aauto-antibodies
utout
o an
oantibodies inn
human myocarditis have undergone IgG class switching, which reflects T helper dependent B
cell responses.
Rodent models have been instructive in further defining how T cells may contribute to
the pathophysiology of myocarditis. Murine viral myocarditis, induced by Coxsackie B infection
of susceptible mouse strains, leads to dilated cardiomyopathy and elevated levels of serum
antibodies specific for cardiac proteins, including ĮMHC. In addition, Rose and colleagues
developed the experimental autoimmune myocarditis (EAM) model, in which immunization with
murine ĮMHC in strong adjuvant results in a self-limiting acute myocarditis followed by chronic
2
DOI: 10.1161/CIRCULATIONAHA.113.003261
dilated cardiomyopathy2. EAM was shown to be dependent on ĮMHC specific CD4+ T cells3 and
the relevant peptide epitope and presenting MHC alleles recognized by these T cells were
subsequently determined4. The presence of ĮMHC specific CD4+ T cells in normal mice, which
can be activated by highly immunogenic delivery of self-antigen, reflects a lack of expression of
the antigen in thymic presenting cells, leading to a failure of central (thymic) tolerance.
Importantly, the same lack of thymic expression of ĮMHC is found in humans, and circulating
ĮMHC-specific CD4+ T cells are found in normal individuals without myocarditis5, suggesting
that peripheral mechanisms of tolerance are required to prevent these T cells from targeting the
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
heart. Lastly, there are likely genetic factors (e.g. HLA type) that also predispose to the failure of
peripheral T cell tolerance to ĮMHC, as evidenced by the fact that only some mo
mouse
ousee sstrains
trrai
ains
ns aare
re
susceptible
usceptible to EAM (e.g. BALB/c but not C57BL/6), and that NOD mice genetically engineered
to
o eexpress
xprress
xp
resss D
DQ8,
Q8, a hu
human class II MHC allele as
associated
sso
s ciated with high
gh ris
risk
sk for
fo type 1 diabetes,
spontaneously
pontaneously
onn
y de
dev
develop
velo
lopp auto
aautoimmune
uto
toim
imm
im
munne myo
m
myocarditis
yocarrdiitis me
m
mediated
diaated
ated bby
yĮ
ĮMHC
MHC
MH
C CD
CD44+ T cells.
cel
ells
l .6
ls
The
Th
he ro
role
l ooff TL
le
T
TLR
LR
R sign
ssignaling
ign
gnal
allin
ing in T ccell
elll res
el
rresponses,
espo
pons
n es
ns
es,, autoimmunity
auto
au
toim
immu
im
muni
mu
nity
ni
t and
ty
and myocarditis
myo
yoca
ca
ard
dit
itis
is
Dendritic cell
ll ((DC)
DC)) ac
DC
acti
activation
tiiva
v ti
tion
on aand
nd aantigen
n ig
nt
gen
n ppresentation
reeseent
n at
a io
i n to nnaïve
a ve T ccells
aï
ells
el
ls iiss a we
well-established
elll-eest
stab
a lished
ab
feature of the innate immune system’s role in promoting T cell responses. DCs recognize and
respond to a variety of danger signals that reflect the presence of infection or tissue damage.
These include pathogen associated molecular patterns (PAMPs), which are present on microbes
but not host cells, and damage associated molecule patterns (DAMPs), which are self-molecules
expressed by infected or otherwise damaged cells. These PAMPs and DAMPs bind to pattern
recognition receptors (e.g. Toll-like receptors (TLRs)) on DCs and promote an increase in
antigen processing, lymph node homing, and the expression of B7 family costimulators and
cytokines, which facilitate naïve T cell activation and differentiation. In fact, the necessity of DC
3
DOI: 10.1161/CIRCULATIONAHA.113.003261
TLR activation for the initiation of strong T cell responses is one reason why immune responses
are not more frequently mounted against healthy tissue, given that central tolerance to many selfantigens, such as Į-MHC, is often incomplete. Autoimmunity may develop, therefore, due to
strong TLR activation of self-antigen presenting DCs that are present at the site of infection or
tissue injury. Indeed, this is the basis for the induction of EAM in mice, whereby peripheral
tolerance is broken in susceptible mouse strains by immunization with peptide fragments of ĮMHC in complete Freund’s adjuvant (CFA), which provides the appropriate innate signaling
necessary to initiate the T cell response.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Evidence for and against a pathologic role of interferon-Ȗ in autoimmune myocarditis
Following antigen presentation by TLR-activated DCs, naïve T cells can differe
differentiate
entia
iaate iinto
ntoo on
nt
onee of
several
everal functional phenotypes, so called helper T cell “subsets”, depending largely on cytokine
cues
cu
ues delivered
del
eliv
iver
iv
ered
er
e at
ed
at the
the time of activation. The twoo primary
p imary pro-inflammatory
pr
pro-infllam
a maato
tory
r subsets are Th1 and
Th17
T
h117
17 cells, which
whhic
ichh are
arre characterized
ch
harrac
acte
teri
te
rize
zeed byy their
theirr pproduction
roduuctionn of th
tthee cy
cytokines
yto
oki
kine
nees in
inte
interferon-Ȗ
teerffer
eron
onn-ȖȖ ((IFNȖ)
IFNȖ) and
an
nd
interleukin-17
nte
terl
rlleu
euki
kinn-17
n17 (IL-17),
(IL-17)
-17)), respectively.
respec
resp
ecctiive
vely
ly. Ea
ly
Each
ach ooff th
these
hes
e e subsets
subset
sub
etss is
et
is thought
tho
h ug
ught
ht too play
pla
layy a unique
u iq
un
iquue role
rolle inn host
hos
ot
defense agai
against
insst in
infection,
nfe
fect
c io
ct
i n,
n w
with
ithh th
it
thee Th
T
Th1/IFNȖ
1//IF
IFN
NȖ aaxis
x s pr
xi
prov
providing
o id
ov
din
ingg im
immu
immunity
m ni
mu
nity
ty against
aga
gain
inst
in
stt viruses
vir
irus
uses
us
es and
intracellular organisms, and the Th17/IL-17 axis combating fungi and extracellular organisms.
In light of its pro-inflammatory role, therefore, it is reasonable to hypothesize that IFNȖ would
act to enhance EAM severity, and indeed some evidence is consistent with this prediction. For
example, IFNȖ producing CD4+ T cells are present in cardiac infiltrates during EAM in mice,
and Į-MHC responding CD4+ T cells found in the blood of myocarditis/dilated cardiomyopathy
patients produce IFNȖ at high levels5, 7. In addition, TCR transgenic mice in which most T cells
are specific for Į-MHC develop spontaneous myocarditis and dilated cardiomyopathy, which is
4
DOI: 10.1161/CIRCULATIONAHA.113.003261
prevented if IFNȖ is blocked or knocked out genetically8; similarly, IFNȖ over-expressing mice
also go on to develop spontaneous chronic myocarditis9.
On the other hand, there is also strong evidence that IFNȖ can play a negative regulatory
role during myocarditis. In viral, parasitic, and autoimmune models of myocarditis in mice,
enhanced disease severity is observed in mice with genetic deficiency of IFNȖ10-12. Likewise, in a
model of myocarditis mediated by CD8+ T cells, IFNȖ deficiency also led to more severe
disease13. Furthermore, many studies have observed an increase in IL-17 driven inflammation in
the absence of IFNȖ, suggesting that Th17 cells may be important for EAM in this setting. In
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
support of this notion, studies using genetic deficiency of molecules critical for Th17
differentiation, such as IL-23 and STAT3, have demonstrated reduced EAM severity
seve
veerity
ity
t 14, 155.
Interestingly,
nterestingly, in another study of EAM, IL-17A deficiency had no effect on acute disease relative
-//
to
o eeither
ithe
it
herr WT (WT
he
WT
T vvss Il17a-/-/ ) or IFNȖ knockoutt mice
mice (Ifng
mic
(
vs If
Ifng
fng
n -/-/-Il
Il17a
Il17
17a-/-/ ), but did produce a
17
clear
cl
leaar reductionn in cardiac
car
arddiac
ac fibrosis
fib
ibro
ro
osi
siss and
an
nd progression
prrogrression
n to
to dilated
dilate
dil
tedd cardiomyopathy
card
ca
rd
dio
omy
myoopat
opathy
hy in
in the
th
he ch
chro
chronic
r ni
ro
nicc
phase
ph
has
a e7. This
This study
stu
tuddy
dy raised
rai
aissed
sed the
the interesting
inte
in
tere
te
rest
re
s in
st
ng possibility
posssib
po
ss bil
i itty that
thaat the
the T
Th1/IFNȖ
h /IFN
h1
/IFN
FNȖȖ and
andd Th17/IL-17
Th1
h17/
7 IL
7/
L-17
-17 axes
ax
xes could
couuld
l
play distinct ro
role
roles
less in ccontrolling
le
ontrol
on
olli
ol
ling
li
ngg tthe
he on
onset
nse
s t an
andd pr
prog
progression
ogre
og
reess
s io
ionn of myocarditis.
myo
y ca
card
rd
dittis
is..
Dendritic cells activate then inhibit myocarditic T cells through IFNȖ, TLR, and NO
dependent pathways
Despite the severity of the disease phenotype observed in EAM as a result of IFNȖ deficiency,
the mechanism of how IFNȖ might restrict the onset of disease is not currently known. Nitric
oxide (NO) has been postulated as a potential mediator due to its established role in T cell
suppression and its clear down-regulation in the absence of IFNȖ. For example, inducible nitric
oxide synthase (iNOS) is upregulated in hearts of mice with EAM, and its expression is
dependent on IFNȖ signaling12. In addition, treatment of WT mice with the iNOS inhibitor L-
5
DOI: 10.1161/CIRCULATIONAHA.113.003261
NAME also caused an increase in disease severity, suggesting a role for iNOS induction in
mediating the inhibitory effect of IFNȖ on EAM12. Interestingly, this finding is consistent with
previous research on experimental autoimmune encephalomyelitis (EAE), the mouse model of
multiple sclerosis, in which IFNȖ induction of iNOS/NO was postulated as a central mechanism
of disease regulation16. Although not addressed specifically in either of these studies, the
plausibility of NO suppression of T cell activation is supported by prior work that suggests a
mechanism involving disrupted STAT5 signaling17.
In this issue of Circulation, Blyszczuk and colleagues present data showing that IFNȖ,
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
TLR, and NO signaling cooperate to limit disease severity in EAM18. This finding is particularly
interesting
nteresting in light of the necessity for dendritic cell TLR activation during the iinitiation
nitiiat
ni
a io
on of
cardiac specific T cell responses in EAM. The authors demonstrate a mechanism for this
negative
ne
ega
gati
tivve
ti
ve rregulation
egul
eg
u attio
ionn that involves NO productionn by so-called “Ti
“TipDCs”,
ipD
p Css”, a monocyte-derived DC
subset
ubsset
e named ffor
orr ttheir
heir
he
ir rob
robust
obus
ob
ustt prod
us
pproduction
rodduc
ucti
tion
on
n off TN
TNF-Į
NF--Į and
d iiNOS
NO
OS th
that
at can
an bbee id
identified
den
enti
tifi
fied
ed bby
y fl
flow
low
ow
hi
cytometry
cyto
cy
tome
to
metr
me
tryy as C
CD68
D688+CD11
CD11b
C
D11bbhi
CD11c
CD11
CD
11cc+. Th
11
Thee au
aauthors
uth
th
hor
o s show
show tthat
hat Ti
ha
T
TipDCs
pDCs
pD
Cs aare
re ppreferentially
reefeere
r nt
ntia
iallyy in
ia
induced
ndu
duce
cedd
in
n EAM follo
following
owi
wing
ng iimmunization
mmun
mm
u iz
un
izat
atio
at
on wi
with
t Į
Į-MHC
-M
MHC aand
nd C
CFA,
FA
A, an
andd ar
aree su
subsequently
ubs
bseq
eque
eq
uent
ue
n ly
nt
y ffound
ound
ou
nd in drainingg
lymph nodes and foci of myocardial inflammation. Along with gp-38+ fibroblasts in the heart,
these cardiac infiltrating TipDCs were shown to be the predominant source of NO present during
EAM. The authors further observed that TipDC generation and NO production was dependent
on IFNȖ signaling, in conjunction with the TLR2 and NFțB dependent activation of monocytes
by heat-killed Mycobacterium tuberculosis (a component of CFA). Through the use of bone
marrow chimeras, the authors go on to show that NO derived from either hematopoietic (e.g.
TipDCs) or non-hematopoietic compartments (e.g. stromal fibroblasts) was sufficient to limit T
cell expansion and EAM severity, whereas only a complete lack of NO resulted in uncontrolled
6
DOI: 10.1161/CIRCULATIONAHA.113.003261
disease. Finally, the authors also observed that IFNȖand TipDC associated TNF-Į exert a
paracrine effect on stromal fibroblasts to increase NO expression, further limiting T cell
expansion and EAM severity. Thus, although TLR activation of DCs is essential for the initiation
of EAM, the study authors nicely show how this process also leads to the development of a DC
subset (TipDCs) that ultimately serves a counter-regulatory role in limiting disease severity.
These findings suggest a model (Figure 1) whereby IFNȖ produced by auto-reactive Th1 cells
contributes both to inflammatory tissue damage in myocarditis and to enhanced TipDC
formation, which in turn suppresses the extent of T cell-mediated tissue damage through NODownloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
dependent mechanisms.
Summary and unresolved questions
The results presented by Blyszczuk and colleagues add to our general understanding that proinflammatory
nfllam
amm
mato
mato
tory
ry molecules
mol
oleecules
ec
in the immune system
m can
can
a also have important
imp
por
o taant counter-regulatory
counter-regulatory
effects.
ef
ffeect
c s. Interes
Interestingly,
stiing
ngly
y, an
n aanti-inflammatory
ntint
i-in
iinfl
in
flam
amma
am
mato
ory eeffect
ffectt ooff DC T
TLR
LR aactivation
ctiv
vat
atio
ion wa
io
was
as also
also ddemonstrated
emon
emon
onst
stra
raateed
recently
ece
cent
ntly
nt
ly in
in a mouse
mouuse
mo
use model
moddel
mo
del off atherosclerosis,
ath
ther
th
erooscl
er
oscllerros
osiis,
is and
and was
was found
fo
oun
undd to result
ressul
ultt from
froom the
the induction
ind
ducti
uc ion ooff
regulatory
egulatory T ccells
ells
el
ls ((Treg)
T eg
Tr
eg))19. Th
Thee po
poss
possibility
ssib
ss
ibil
ilit
il
itty th
that
a T
at
Treg
regg re
re
rresponses
spon
sp
onse
on
s s ar
se
are en
enha
enhanced
hanc
ha
nced
nc
ed bby
y TL
TLR/
TLR/NO
R NO
R/
dependent mechanisms in EAM was not explored in the current study but would represent an
interesting future direction of research. In addition, the role of other T cell inhibitory pathways in
EAM, which are known to be upregulate IFNȖ were not explored in the current paper. For
example, IFNȖ strongly induces expression of programmed death ligand 1 (PD-L1), a wellknown co-inhibitory molecule that can be expressed both by antigen-presenting and stromal
cells. Through interaction with its co-receptor PD-1, PD-L1 limits TCR-mediated activation of
T cells and has been shown to reduce disease severity in CD8+ T cell myocarditis and in EAM13,
20
. Although it is difficult to know to what extent these mechanisms contribute to the control of
7
DOI: 10.1161/CIRCULATIONAHA.113.003261
myocarditis relative to TipDC mediated NO production, it is likely that multiple and sometimes
overlapping mechanisms may work in concert to protect against autoimmunity. Of interest in
this regard is a prior study showing that disruption of PD-L1/PD-1 signaling in macrophages
resulted in increased T cell IFNȖ production but decreased T cell proliferation21. This seemingly
contradictory observation was reconciled by the finding that increased IFNȖ expression also led
to a robust induction of macrophage iNOS and NO production, which in turn inhibited T cell
proliferation. In any case, the study by Blyszczuk and colleagues highlights the fact that
therapeutic strategies for immunological diseases require a careful consideration and
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
manipulation of the balance between the activating and regulatory effects of specific immune
pathways. In particular, research into the human relevance of TipDC biology is llacking
acki
k ng aand
ki
nd
would represent a critical first step in translating the current findings for eventual clinical
application.
ap
ppl
plic
icat
ic
atio
at
ion.
io
n.
Funding
Fu
und
ndin
ng So
Sour
Sources:
u cees:: This
ur
Th
hiss study
stu
tuddy
dy was
was supported
sup
ppoort
rteed by
by National
Nati
Na
tioona
onal
al Institutes
Ins
nsti
titu
tu
utees of Health
Hea
ealt
lthh grant
lt
gran
gr
an
nt
R01HL087282
(AHL).
R01H
1HL0
L087
8728
2 2 (A
(AHL
HL).
)
Conflict of Interest Disclosures: None.
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0. Fairweather
Fair
Fa
irwe
ir
weeat
athher D,
D, Frisancho-Kiss
Frisancho-Kiss S, Yusung SA,
SA
A, Barrett
Barrett MA, Davis
Daaviss SE,
SE, Gatewood SJ, Njoku
DB,
Rose
NR.
myocarditis
DB
B, R
ose N
R. IInterferon-gamma
nter
nt
e fe
er
fero
ro
onn-ga
gamm
ga
mm
ma pr
pprotects
otec
ot
ects
ts aagainst
g in
ga
inst
st cchronic
hroni
niic vi
vviral
rall my
myoc
ocar
ardi
d tis by rreducing
di
e uc
ed
ucin
ingg ma
mast
s ccell
st
el
degranulation,
transforming
factor-beta
degran
degr
a ulation,
n fibrosis,
fib
i rosi
siis, and
and the
the profibrotic
pro
roffibr
fibrrotic cytokines
cyttokine
nes tr
ne
ran
nsfforrmi
minng
ng ggrowth
rowt
ro
wthh fa
wt
fac
ctor-b
ctor
-bet
-b
etaa 1,
et
1
interleukin-1
Pathol.
nteerleukin-11 beta,
b ta,
be
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Figure
Legend:
Figu
Fi
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re L
egen
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end:
d:
Figure 1. Schematic representation of the model proposed by Blyszczuk and colleagues for nitric
oxide (NO) mediated negative regulation of autoreactive T cells by tumor necrosis factor alpha
(TNF-Į and inducible NO synthase producing dendritic cells (TipDCs) during autoimmune
myocarditis. First, conventional dendritic cells (DCs) present antigen (Į-myosin peptide) to naïve
CD4+ T cells with a specific T cell receptor. In the presence of toll-like receptor (TLR)
activation by pathogen associated molecular patters (PAMPs) or damage associated molecular
patterns (DAMPs), DCs will provide the appropriate co-stimulatory (e.g. B7) and cytokine
10
DOI: 10.1161/CIRCULATIONAHA.113.003261
signals (e.g. IL-12) to promote the differentiation of naïve CD4+ cells into effector T cell
subsets, such as T helper type 1 cells (Th1). Th1 cells then produce high levels of interferon
gamma (IFN-Ȗ), which in turn acts to promote the differentiation of monocytes into
CD64+CD11bhiCD11c+ TipDCs in conjunction with TLR2 activation. TipDCs then produce NO
directly, and through indirect mechanisms involving TNF-Į activation of stromal fibroblasts. NO
then acts to prevent effector T cell activation and clonal expansion, thus limiting the extent of Tcell mediated myocardial damage.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
11
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Two Sides to Every Pro-Inflammatory Coin: New Insights into the Role of Dendritic Cells in the
Regulation of T-Cell Driven Autoimmune Myocarditis
Gabriel K. Griffin and Andrew H. Lichtman
Circulation. published online May 13, 2013;
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
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