European Heart Journal Advance Access published December 8, 2015

European Heart Journal REVIEW

doi:10.1093/eurheartj/ehv639

Basic science for the clinician

Role of T-cells in myocardial infarction

Ulrich Hofmann 1,2 and Stefan Frantz 1*
1
Klinik und Poliklinik für Innere Medizin III, Universitätsklinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Straße 40, Halle (Saale) 06120, Germany; and
2
Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Straubmühlweg 2a, Würzburg 97078, Germany

Received 6 July 2015; revised 4 November 2015; accepted 4 November 2015

Innate immunity has been studied for several decades in the context of ischaemia-reperfusion injury, myocardial remodelling, and healing. In the

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last years, a number of experimental and clinical studies focused on adaptive immunity in these processes. Meanwhile, there is considerable
evidence especially on the role of CD4+ T-cells in myocardial injury and healing, whereas their role in remodelling is less clear. Innate leukocytes
are able to recognize a wide array of self and foreign molecular patterns, whereas the activation of adaptive immunity requires the highly specific
cooperation of antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. Relevant autoantigens have not yet been def-
initely identified but experimental evidence indicates that autoantigen recognition is necessary for T-cell activation after myocardial infarction.
Non-antigen-specific modes of activation might also play a role especially during acute ischaemia and reperfusion of the myocardium. This
review summarizes the current evidence from experimental studies and presents side-by-side recent clinical data on the role of T cells in
the pathophysiology of myocardial reperfusion injury and post myocardial infarction healing.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Innate immunity † Adaptive immunity † Myocardial infarction † Atherosclerosis † Lymphocyte

and the clinical significance regarding potential therapeutic implica-

Introduction
Atherosclerosis constitutes the pathophysiological basis for disab-
ling diseases like stroke and myocardial infarction, both constituting
the leading causes for morbidity and mortality in the Western
World.1 Myocardial infarction is one of the most detrimental ath-
erosclerosis related complications leading to considerable mortality
and morbidity due to heart failure. Despite the encouraging effects
of the current state-of-the-art primary and secondary prevention
measures, there remains a substantial residual risk for ischaemic
complications in individuals with sub-clinic or manifest coronary
heart disease.2 Furthermore, it is now widely accepted that despite
prompt reperfusion, which is today achieved in the majority of our
patients, the myocardium is subject to additional injury induced by
re-establishment of blood flow.3 The role of innate immunity has
been a subject for experimental research in the field of atheroscler-
osis and myocardial ischaemia-reperfusion injury for decades
whereas T-cells have only recently come into focus.
Therefore, the present review summarizes established knowl-
edge regarding the role of T-cells in the pathogenesis of myocardial
ischaemia-reperfusion injury and post myocardial infarction healing.
A special focus will be on the juxtaposition of mechanistic concepts
mainly derived from rodent studies and the relating recent data from
human specimens. Current knowledge gaps, inherent problems in
the transfer from small animal data to human pathophysiology,
tions will be discussed.
Basic principles of T-cell activation
For the better understanding of the data summarized below, we first
would like to briefly envision some basic principles of T-cell gener-
ation, migration, and age-related changes in T-cell function. The cen-
tral organ for the generation of T-cells is the thymus. The current
nomenclature of T-cell subsets is based on several markers (Table 1)
which are mostly analysed by fluorescence-activated cell sorting
(FACS). The thymic release of naı̈ve CD4+ and CD8+ T-cells
declines with age.4 The process of thymus involution starts in
human childhood which is much earlier than observed in mice.5
This is associated with an age-dependent decline in the T-cell recep-
tor diversity and the predominance of highly differentiated periph-
eral memory T-cells within an ‘aged’ T-cell compartment. The
age-related changes in the memory T-cell repertoire underlies a
strong modulation by chronic virus infection especially cytomegaly
virus (CMV). Cytomegaly virus infection, having an age-dependent
prevalence of 70% in Western world, induces an expansion of
the so-called effector-memory CD4+ and CD8+ compartment
coming along with a shrinkage of the T-cell receptor diversity.5
The memory T-cell subsets in elderly are poised for proinflamma-
tory cells which is aggravated by both CMV infection and traditional

* Corresponding author. Tel: +49 345 557 2601, Fax: +49 345 557 2072, Email: stefan.frantz@uk-halle.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
Page 2 of 7
Table 1 Key markers for immuno-phenotyping of
T-cells referred in the text
CD Cluster of differentiation nomenclature denotes surface
markers for the immune-phenotyping of cells
CD4 CD4 antigen mainly identifies T-helper cells
CD8 CD8 antigen mainly identifies cytotoxic T-cells
CD25 Subunit of the interleukin-2 receptor, expressed on
activated T-cells and CD4+ T-regulatory T-cells
Foxp3 Forkhead-Box-Protein 3 transcription factor serves
as marker for CD4+ T-regulatory cells in mice
CD39 Ectonucleoside triphosphate diphosphohydrolase,
membrane bound enzyme hydrolyzes ATP and
ADP to AMP
CD73 ecto-5′ -nucleotidase, membrane bound enzyme converts
AMP to adenosine
cardiovascular risk factors. These processes are only poorly re-
flected in rodent models.
For adaptive immune responses, naı̈ve T-cells have to recognize
their antigens in the context of major histocompatibility complex
surface molecules. This process takes place in secondary lymphatic
organs, mainly in the draining lymph nodes and the spleen. Besides
antigen recognition, additional stimuli are required for activation of
T-cells (‘costimulatory signals’). T-cell activation by contact with its
specific antigen is called T-cell priming. Primed CD4+ and CD8+
T-cells can then both exert effector/proinflammatory and regula-
tory/anti-inflammatory function depending on their differentiation
profile which is defined by the signals the T-cell receives from
antigen-presenting cells and the environment in lymphatic organs.
So-called natural CD4+ regulatory T-cells constitute a particular
anti-inflammatory immune-regulatory T-cell subset which is gener-
ated in the thymus and is highly enriched for T-cells with autoantigen
specificity.
Principles of T-cell migration
In adults, memory T-cells predominate the peripheral T-cell com-
partment which upon antigen recognition are poised for rapid pro-
liferation and effector function execution. T-cells enter lymph nodes
either from the afferent lymphatics or from the blood and exit
lymph nodes via the efferent lymph which is mainly collected in
the thoracic duct where it is drained to the blood. Naı̈ve T-cells re-
circulate between blood and lymph nodes. Also different subsets of
the memory T-cell pool recirculate through the body in steady state.
Antigen-presenting cells collect antigens in peripheral tissues and
lymph nodes to present them as processed peptides to T-cells.
T-cell activation by recognition of antigens leads to the transient re-
tention of T-cells in secondary lymphoid organs. However, the ac-
tivation and clonal expansion of antigen experienced T-cells is
coupled with migration cues enabling activated T-cells to leave sec-
ondary lymphoid organs and to become recruited to sides of inflam-
mation.6 Both transient T-cell retention in secondary lymphatic
organs for efficient antigen recognition and activation and recruit-
ment to peripheral non-lymphatic organs is strongly regulated by
chemokine receptor signalling. Hereby, the location of T-cell
U. Hofmann and S. Frantz
priming is believed to mainly influence the pattern of their periph-
eral homing.7 For the myocardium, hepatocyte growth factor signal-
ling via its receptor c-Met was recently shown to instruct primed
T-cells in heart draining lymph nodes to express a pattern of chemo-
kine receptors, including CCR4 and CXCR3, which allow their spe-
cific homing to the myocardium.8 After antigen recognition, clonally
expanding T-cells develop into tissue-homing effector cells and dif-
ferent memory T-cell subsets which are defined by their recircula-
tion characteristics. Besides recirculating memory T-cell subsets
tissue resident memory cells are becoming more and more recog-
nized in different organs including the myocardium9 which cannot
be monitored in peripheral blood. Their biological significance in
myocardial homeostasis and disease is still enigmatic.
The very brief summary of the biological principles of T-cell acti-
vation and migration should illustrate that analysis of the peripheral
blood alone will allow studying certain subsets of recirculating
T-cells which, at best, contain only a very small portion of disease-
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specific cells (Figure 1). This poses a major limitation in the interpret-
ation of data from a considerable number of studies analysing T-cells
in peripheral blood. However, it is obvious that tissue specimen
from the myocardium or its draining lymph nodes which would pro-
vide much more specific insights are not widely available.
Clinical evidence for the
involvement of T-cells in acute
coronary syndromes
There is meanwhile a considerable number of studies that have ana-
lysed T-cells in peripheral blood in patients with unstable angina or
acute coronary syndromes. These data might partly reflect activa-
tion of T-cells secondary to coronary atherothrombosis and pre-
ceding coronary artery wall inflammation. However, they might
also represent system-wide changes in the T-cell activation status
and their migratory behaviour in response acute myocardial injury
and failure. Activation of the renin – angiotensin – aldosterone or
the sympathetic nervous system is also likely to influence the com-
position of the circulating T-cell subsets analysed in the periphery.
Hence, specific peripheral T-cell patterns observed in patients
with acute coronary events may not necessarily be informative on
the role of particular T-cell subsets in the pathophysiology of ather-
othrombosis or myocardial injury. For space restrictions, we would
like to refer the reader to a very recent comprehensive review on
clinical studies describing T-cell subsets in patients with atheroscler-
osis and acute coronary syndromes.10
Role of T-cells in
ischaemia-reperfusion injury
of the myocardium
Experimental evidence from mouse
studies
First experimental evidence that CD4+ T-cells contribute to myo-
cardial ischaemia-reperfusion injury came from a study analysing
wild-type and lymphocyte-deficient RAG1 KO mice. RAG1 KO
Role of T cells in myocardial infarction
Figure 1 T-cells migration and recirculation pathways. The scheme depicts where particular T-cells subsets get accessible for analysis in experi-
mental and clinical studies.
mice revealed significantly smaller infarct sizes compared with
control mice. Furthermore, CD4+ T-cell-depleted mice, but not
CD8+-depleted mice showed a significantly decreased infarct size
compared with control mice. Reconstitution of RAG1 KO mice
by adoptive transfer with CD4+ T cells reversed this protection
seen in RAG1 KO mice. RAG1 KO mice reconstituted with
CD4+ T-cells from IFN-g KO mice did not increase myocardial
infarct size, indicating that CD4 + T-cells promote ischaemia-
reperfusion injury by IFN-g expression.11
The involvement of T-cells in ischaemia-reperfusion injury has
been studied in animal reperfusion injury models in several organs
but there are few data explaining how CD4+ T-cells become acti-
vated under these conditions.12 The timeframe in which myocardial
injury occurs in the presence of CD4+ T-cells would rather indicate
a non-T-cell receptor dependent way of T-cell activation, e.g. by rec-
ognition of ‘alarmins’13 from injured cell which are recognized by
pattern recognition receptors, such as toll-like receptors.14
Role of adenosine signalling and
T-regulatory cells for protection against
reperfusion injury
In the reperfused myocardium, the ectoenzymes CD39 and CD73
are expressed by a broad range of leukocytes and cardiomyocytes.15
They promote the extracellular degradation of nucleotides released
by cellular injury to anti-inflammatory adenosine. Treatment with an
adenosine (A2A) receptor agonist blocked the increase in infarct
size in Rag1 KO mice reconstituted with wild type but not A2A re-
ceptor deficient CD4+ T cells.11 This observation indicates that the
Page 3 of 7
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injurious action of CD4+ T-cells can be mitigated by endogenous
adenosine signalling.
Corresponding to the above-mentioned clinical data,16 CD4+
T-regulatory cells were recently reported to rapidly accumulate
in murine hearts following ischaemia-reperfusion. The adoptive
transfer of in vitro activated T-regulatory cells was able to decrease
myocardial injury, whereas transfer of non-activated T-cells had
no effect. Mechanistically, the protective effect of activated
T-regulatory cells was related to ectonucleoidase (CD39) ex-
pression.17 From these data, one can speculate that recruitment
of (in vitro) activated T-regulatory cells adds to the local
CD39-mediated adenosine formation which counteracts the dele-
terious effects of other leukocytes subsets, including conventional
T-cells in the context of myocardial ischaemia-reperfusion.
Clinical evidence for the involvement of
T-cells in myocardial reperfusion injury
There are only few studies assessing the kinetics of blood T-cell sub-
sets during early reperfusion. A novel approach using 13-parameter
FACS immuno-phenotyping followed by hierarchical cluster analysis
was applied to identify novel subsets of peripheral T-cells in patients
with acute STEMI.18 This study reported a specific loss of CD4+
chemokine receptor CCR7+ T-cells during early reperfusion. These
subsets include naı̈ve, central memory, and T-regulatory cells. At the
moment, one can definitely not clarify whether this observation re-
flects a CCR7-mediated redistribution of this T-cell subset to per-
ipheral (lymphatic) organs or a specific accumulation of these
subsets in the reperfused microvascular bed of the myocardium.
Page 4 of 7
However, for the interpretation of the data, it is important to men-
tion that CCL19 and CCL21 are the ligands for CCR7. Both chemo-
kines are reported to rise in plasma following coronary
interventions.19 Thus, it is conceivable that these CCR7 ligands
could play a role for the recruitment of T-cells to the reperfusion
myocardium. The authors further concentrated their in-depth ana-
lysis on a subset of CD57+ T-cells likely resembling memory T-cells
which have recently undergone proliferation. Unfortunately,
T-regulatory cells which have been described to specifically
accumulate in coronary thrombi16 were not further analysed in
this study.
T-cell retention within the myocardium is reflected by trans-
coronary gradients. By such an experimental approach, a possible
mechanistic hint for the injurious role of effector-memory T-cell re-
tention in acutely reperfused myocardium was provided: the extent
of T-cell retention in the coronary circulation correlated with
microvascular obstruction as determined by cardiac magnet re-
sonance tomography imaging.20 One of the chemokines potentially
mediating retention of T-cells in the reperfused microvascular
bed might be fractalkine. Its receptor (CX3CR1) expression after
reperfusion was especially regulated in the subset of CCR72 effect-
or T-cells.20
Recently, the same group reported data on the CD8+ T-cell com-
partment in patients with reperfused MI. They found a particular
early and long-lasting fall in the peripheral frequency of terminally
differentiated effector-memory CD8+ T-cells in CMV-positive pa-
tients.21 The CD8+ subset that was depleted from peripheral blood
included CMV-specific T-cells. Their data further indicate that the
surface molecule PD-1 might be involved in the long-lasting loss
of this subset which was specifically found in CMV-positive patients.
Whether the putative preferential recruitment of this CD8+ T-cell
subset to the reperfused myocardium impacts reperfusion injury
and clinical outcome remains to be determined. Of note, a longitu-
dinal cohort study found a significant association of coronary artery
disease-related mortality and CMV status suggesting a potential
mechanistic link between the changes in the CD8+ T-cell compart-
ment induced by CMV infection and the pathophysiology of acute
coronary events.22
Collectively, there is consistent evidence from mouse studies that
proinflammatory CD4+ T-cells contribute to ischemia-reperfusion
injury whereas the role of CD4+ T-regulatory T-cells which were
found to be enriched in coronary thrombi is less well established.
However, the available experimental data indicate that they might
constitute a therapeutic target to mitigate myocardial ischaemia-
reperfusion injury. Data from clinical studies further indicate that
besides CD4+ T-cells, CD8+ memory T-cell subsets become
entrapped in the coronary microcirculation early after the onset
of reperfusion and/or might even actively infiltrate the reperfused
myocardium where they likely contribute to reperfusion.
Role of lymphocytes in non-
reperfused myocardial infarction
Experimental evidence on CD41 T-cells
First experimental evidence for the activation of T-cells with reactiv-
ity to myocardial autoantigens in response to experimental MI came
U. Hofmann and S. Frantz
from a study demonstrating that adoptive transfer of splenocytes
from rats after acute myocardial infarction produced myocarditis
in naı̈ve recipient rats.23 Inspired by this study, we recently demon-
strated in a mouse MI model that CD4+ T-cells get activated and
proliferate in heart draining lymph nodes.24 The activation process
takes place within days and requires an intact T-cell receptor reper-
toire. Absence of CD4+ T-cells in CD4 deficient and MHC class II
deficient mice was associated with worse outcome. A similar
phenotype was found in a mouse model harbouring a transgenic
T-cell receptor for an in this context irrelevant ovalbumin-derived
peptide (OT-II mouse) which showed no significant T-cell activation
in mediastinal lymph nodes in response to MI. The most likely inter-
pretation of the data is that the presence of CD4+ T-cells that can
be activated by autoantigens presented by MHC class II molecules is
a prerequisite for proper wound healing. The pivotal role of T-cells
activated by interaction with antigen-presenting cells was indirectly
proven in another experimental study where CD11c+ cells, mainly
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representing antigen-presenting cells, were ablated in a transgenic
mouse model.25 After MI there was a strikingly similar phenotype
as found in CD4+ T-cell deficient mouse models. Absence of
CD11c+ cells resulted in deteriorated left ventricular function and
remodelling after MI. However, the effect of CD11c + antigen-
presenting cells on the activation of CD4+ T-cells was not further
explored in this study.
A major open question in the field is whether CD4+ T-cells re-
spond to tissue-specific antigens or ‘universal’ tissue autoantigens.
Mainly for methodological reasons it has not yet been experimental-
ly addressed which antigens activate T-cells in experimental models
of ischaemic tissue injury like MI.
Our experiments in mice showed that both conventional effector
CD4+ T-cells having mainly a Th1 cytokine profile and Foxp3+
T-regulatory cells infiltrate the myocardium within a few days after
MI.24 However, the exact pathophysiological role of conventional
and regulatory T-cells in myocardial healing was initially not clear.
Another group then reported in this context that T-regulatory
cell function is compromised in mice that underwent experimental
infarction.26 Therefore, we concentrated our studies on the differ-
ential effects of both CD4+ T-cell subsets.
Mechanistically, we found that CD4+ T-cells control the infiltra-
tion and most likely the differentiation of recruited proinflammatory
monocytes, characterized by high surface expression of the antigen
Ly6C. The absence of CD4+ T cells increased the number of Ly6-
Chigh monocytes in the infarcted myocardium.24 Depletion of CD4+
T-regulatory cells induced a preferential M1-like phenotype, where-
as activation of T-regulatory cells induced a M2-like phenotype in
myocardial macrophages. Stimulation of M2-like macrophage differ-
entiation by activation of T-regulatory cells induced expression of
arginase-1, Interleukin-13, osteopontin, and TGF-b in macro-
phages.27 As these proteins are all involved in the extracellular ma-
trix formation, the control of macrophage differentiation likely
constitutes the main mechanism how T-regulatory cells improve
myocardial healing. Accordingly, CD4+ T-cell deficient mice
showed disturbed extracellular matrix formation in the scar and
died from myocardial rupture. Another experimental study in the
mouse MI model reported data fitting well to our concept that
T-regulatory cells may modulate the fibroblast phenotype and func-
tion in the infarcted myocardium.28 Further adding to the concept of
Role of T cells in myocardial infarction
a pivotal role of regulatory T-cell in myocardial post infarct healing, it
was recently reported that expansion of T-regulatory cells in vivo by
means of either adoptive transfer of Tregs or a CD28-superagonistic
antibody attenuated myocardial proinflammatory cytokine expres-
sion and immune cell infiltration in a rat MI model.29 Accordingly an-
other group reported that adoptive transfer of Treg cells in a mouse
permanent MI model attenuates both the post-infarction inflamma-
tory response and adverse remodeling.30 Collectively, endogenous
T-regulatory cells emerged as pivotal cellular players regulating re-
pair of the myocardium. The precise mechanism and location of
their interaction with myeloid progenitors, monocytes, and macro-
phages represent major gaps in our understanding of these inter-
action processes.31 A schematic summary on the local action of
CD4+ T-cells in infarcted myocardium is presented in Figure 2.
Experimental evidence on CD81 T-cells
Concerning the role of CD8+ T-cells, a subset of angiotensin 2 recep-
tor positive CD8+ T-cells was described in the peri-infarct zone of
rats 7 days after MI.32 This subset of CD8+ T-cells differed from clas-
sical cytotoxic angiotensin 2 receptor negative CD8+ T-cells in their
capacity to secret IL-10 in response to angiotensin 2 stimulation
in vitro. Their functional significance in myocardial healing was demon-
strated by transfer of these cells harvested from a donor after MI. This
procedure significantly reduced infarct size after experimental MI.
Correspondingly, the beneficial action of angiotensin 2 receptor ex-
pressing CD4+ T-cells which includes a subset of Foxp3+ T-cells was
recently reported.33 Of note, animals with genetic CD8 deficiency
showed no significant clinical phenotype after experimental MI com-
pared with WT animals (own unpublished data).
Evidence from human studies
Histopathological analysis of myocardial specimen and non-invasive
imaging modalities would be highly valuable to judge the relevance
of the reported changes in the T-cell compartment in peripheral
blood for myocardial injury and subsequent healing processes.
Figure 2 Role of conventional (Tconv) and regulatory (Treg) CD4+ T-cells and their interaction with other cell types in experimental models of
reperfusion injury and myocardial healing.
Page 5 of 7
However, at present there are no clinically applicable non-invasive
imaging techniques to monitor T-cell migration. Histopathological
studies reported T-cell infiltrates in both remote and peri-infarction
myocardial regions and activated T cells within the coronary artery
wall of both the infarct- and non-infarct-related arteries in necropsy
specimen from patients suffering from MI.34 This gives a valuable hint
that, in analogy to what was observed in mouse studies, myocardial
injury in humans activates T-cells which home to the injured myo-
cardium and likely modulate local inflammatory activity. Only one
clinical study comparatively analysed thoracic lymph nodes from pa-
tients with acute coronary syndromes and control individuals. How-
ever, the authors could not find differences in the cellular
composition of lymph nodes between the two cohorts.35 Thus,
more data on T-cell activation and differentiation parameters
from human tissue specimen would be highly valuable to decipher
the role of T-cells post myocardial infarction.
Collectively, there is substantial experimental evidence showing
that CD4+ T-cells, especially T-regulatory cells promote myocardial
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healing by interaction with macrophages and probably fibroblasts.
Mostly due to methodological limitations, there are no clinical data
to support this beneficial role of CD4+ T-cells which is obviously con-
trary to their immediate detrimental action during early reperfusion.
Conclusion
The available experimental data from animal models provide us a
relative clear picture regarding the role of CD4+ T-cells: In the
mouse ischaemia-reperfusion model CD4+ T-cells aggravate
ischaemia-reperfusion injury. Subsequently, the activation of
CD4+ T-cells, most likely by recognition of autoantigens, is required
for proper healing. In this context, especially the subset of Foxp3+
CD4+ regulatory T-cells tunes the differentiation of macrophages
towards a pro-healing phenotype preventing from left ventricular
dilation and rupture. However, the role of newly primed effector
T-cells, recirculating, and tissue resident memory T-cells has not
Page 6 of 7
Figure 3 Mechanism of activation and recruitment of T-cells to the post-ischaemic myocardium. Mechanism of immediate T-cell retention in
reperfused myocardium, chemokines/chemokine receptors determining homing of antigen-specific activated T cells, and factors controlling the
local retention in myocardium are largely unknown but might all constitute putative therapeutic targets.
yet been addressed in this context. Also, the role of T-cells in later
stages of remodelling is not clear. For identifying therapeutic ap-
proaches targeting T-cells to be further evaluated towards clinical
application, we need to identify relevant antigens inducing T-cell ac-
tivation and to understand which signals induce their recruitment to
and retention in the infarcted myocardium (Figure 3).
However, regarding the particular differences in the T-cell com-
partment of humans and laboratory rodents we have to be cautious
in translating the findings from experimental studies to the clinical
scenario. The immune system of our patients shows phenomena
subsumed under the term ‘immune-senescence’ that are not pre-
sent in our laboratory animals. Further, subsets like CD4+ CD28null
T-cells which emerge in patients with chronic low-grade inflamma-
tion, e.g. associated with atherosclerosis36 can exert proinflammatory
function without T-cell receptor ligation. These unconventional
T-cells are widely missing in our laboratory mice but might especially
contribute to atherothrombosis and reperfusion injury in humans.
Thus, we further need a deeper understanding how, when, and
which T-cell subsets are recruited to the human coronary microvas-
culature and subsequently to the reperfused myocardium. Also, we
should not only focus on the ischemic myocardium but also on
draining lymph nodes and other lymphatic organs including the
spleen and bone marrow where interactions with other cellular
components of immunity and haematopoiesis might take place in
our patients. Therefore, a joint effort of cardiologists, immunolo-
gists, and imaging specialists is warranted for designing new ap-
proaches to be tested in translational and clinical studies. They
should enable us to get deeper insights in the implications of
T-cell activation in the clinical context and to validate new thera-
peutic approaches aiming at the modulation of T-cell immunity.
Authors’ contributions
S.F. handled funding and supervision; S.F., U.H. drafted the manu-
script; S.F., U.H. made critical revision of the manuscript for key
intellectual content.
U. Hofmann and S. Frantz
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Funding
The manuscript was supported by grants of the Deutsche Forschungsge-
meinschaft (DFG SFB688 to U.H. and S.F.) and by the Bundesministerium
für Bildung und Forschung (BMBF01 EO1004 to S.F.).
Conflict of interest: none declared.
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