Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis
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Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.
KeywordsHeart Myocarditis Effector CD4+ T cells Cardiac fibrosis Th17 lymphocytes Dilated cardiomyopathy Experimental autoimmune myocarditis
Experimental autoimmune myocarditis
Alpha-myosin heavy chain
Complete Freud’s adjuvant
Naïve/effector CD4+ T cell
T cell receptor
Antigen presenting cell
Common gamma cytokines
CD4+ T helper cell
Myocarditis most commonly results from cardiotropic infections or tissue damage, followed by the activation of heart-specific autoimmunity [3, 34]. Lymphocytic myocarditis, characterized by extensive infiltration of lymphocytes and monocytes with signs of cardiomyocyte necrosis, represents the most common type of the disease . Clinical presentation of the disease ranges from acute or chronic to fulminant myocarditis . In about one-third of biopsy-proven cases, myocarditis progresses to dilated cardiomyopathy (DCM), characterized by extensive fibrosis, ventricular dilation and heart failure [9, 14]. The mechanisms underlying variable clinical outcomes of myocarditis remain, however, poorly understood.
Mouse models of experimental autoimmune myocarditis (EAM) reflect key aspects of the human disease . In the classical EAM model, immunization with alpha-myosin heavy chain (α-MyHC) peptide and complete Freund’s adjuvant (CFA) induces myocarditis in susceptible mice. On follow-up, inflammation in the myocardium resolves and some mice develop progressive cardiac fibrosis, ventricular dilation and heart failure [4, 5, 21]. In the α-MyHC/CFA model, autoreactive CD4+ T cells play a central role in disease induction. Mechanistically, circulating α-MyHC-reactive CD4+ T cells, which escape the negative selection in the thymus  set the biological basis for EAM development. Following α-MyHC/CFA immunization, antigen-presenting cells (APCs) activate α-MyHC-reactive CD4+ T cells. During the initial phase, naïve CD4+ T (Tn) cells become activated with antigen in the lymphatic system, where they undergo phenotypic changes. Tn cells convert into the effector (Teff) phenotype, expand and acquire new migratory properties . In the effector phase, α-MyHC-reactive Teff migrate into cardiac tissue, where they re-encounter α-MyHC antigen. This antigen-dependent response in the heart triggers production of proinflammatory cytokines, which induce myocarditis. Accordingly, adoptive transfer of CD4+ T cells isolated from α-MyHC/CFA immunized mice can convey disease from the host to recipient [30, 36]
The adverse post-inflammatory remodeling, including an excessive fibrotic response, characterizes progression of myocarditis to DCM and end-stage heart failure [6, 19]. In fact, accumulation of cardiac fibroblasts and their transformation into myofibroblasts is the hallmark of cardiac fibrosis . CD4+ T cells and particularly the Th17 subset have been implicated in transition from myocarditis to DCM phenotype [2, 29]. Insight from other models also points to autoreactive CD4+ T cells as key mediators of cardiac fibrosis [15, 26].
In contrast to well-defined antigen-dependent responses, our understanding of antigen-independent mechanisms of CD4+ T cells is limited. It has been demonstrated that such antigen-independent stimulation of Teff, called also a bystander activation, could effectively contribute to CD4+ T cell expansion and function in a specific inflammatory condition . Innate stimuli [18, 32] and cytokines of the common gamma family (γc-cytokines IL-2, IL-7, IL-15 and IL-21)  have been recognized as mediators of the bystander activation of CD4+ T cells. So far, however, the role of antigen-independent mechanisms and heart non-specific CD4+ T cells in myocarditis remained elusive.
EAM induction and adoptive T cell transfer
EAM was induced in 6–8 weeks old BALB/c or CD45.1-tg mice using an established protocol (see Supplemental Methods). In respective experiments, EAM mice were injected intravenously with either DO11.10+ Teff, DO11.10+ Tn or TCR-M Teff (3–5 × 106 per mouse) on days 17 and 20. For adoptive transfer, 6–8 weeks old BALB/c mice were sub-lethally irradiated (5.5 Gy) using a Gammatron (Co-60) and intravenously injected with 3–5 × 106 CD45.1+ Teff, TCR-M Teff and/or DO11.10+ Teff per mouse. Sublethal irradiation depletes host’s T cells and thereby enables efficient engraftment and propagation of adoptively transferred T cells. Mice were euthanised by exposure to > 70% carbon dioxide or anesthetic overdose. All animal experiments were approved by local authorities and performed in accordance with Swiss federal and Polish law and the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (NIH Publication, 8th Edition, 2011).
Generation of Teff
Erythrocyte-lysed splenocytes/iLN cells were isolated from α-MyHC/CFA immunized CD45.1-tg mice at day 17 (CD45.1+ Teff), untreated TCR-M-tg (TCR-M Teff) or untreated DO11.10-tg (DO11.10+ Teff) mice. Teff were generated by ex vivo CD4+ T cell activation with the respective antigen in the presence of APCs for 72 h (see Supplemental Methods). Activated CD4+ T cells purified by MACSorting using mouse anti-CD4 magnetic beads (Miltenyi) were used as Teff for adoptive transfer experiments. For in vitro use, Teff isolated from spleens/LN and hearts were additionally purified by FACSorting for CD4+CD44hiCD62Llow cells. Tn were isolated from spleens of DO11.10-tg mice and purified using CD4 positive MACSorting and FACSorting for CD4+CD44lowCD62Lhi cells using FACS Aria III.
Human CD4+ T cell subsets were sorted from peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood buffy coats of healthy donors (Blutspende Zurich, Switzerland), obtained with informed consent in accordance with the Declaration of Helsinki. PBMCs were isolated using Lympholyte (Cederlane) density gradient separation according to manufacturer’s instructions. CD4+ T cells were enriched by MACSorting using human anti-CD4 magnetic beads (Miltenyi). CD4+ T cell subpopulations were further sorted using FACS Aria III (BD Bioscience) based on the respective surface marker phenotypes: CD45RA+CD45RO−CCR7+CD27+ (Tn) and CD45RA−CD45RO+CCR7−CD27− (Teff).
CD4+ T cell proliferation
CD4+ T cells were isolated from mouse erythrocyte-lysed splenocytes/LNs or human PBMCs by MACS or sorted from hearts digested with Liberase (Roche). CD4+ T cell subpopulations were isolated using FACS Aria III. Cells were labeled with 2.5 μM CFSE or 5 μM CellTrace Violet Cell Proliferation Kit (both Life Technologies) and either injected into recipient mice or cultured in vitro in the respective conditions (see Supplemental Methods). Cell proliferation was analyzed with LSRII Fortessa analyzer (BD Bioscience) and FlowJo software (Tree Star) using the Proliferation platform.
CD4+ T cell and cardiac fibroblast co-culture
CD4+ T cell subpopulations were isolated from mouse or human CD4+ T cell fractions with FACS Aria III cell sorter and cultured on confluent mouse or human cardiac fibroblasts, respectively (see Supplemental methods).
Flow cytometry and cell sorting
Single cell suspensions were prepared either from digested mouse hearts, erythrocyte-lysed splenocytes/LNs, or mouse and human PBMCs (see Supplemental methods). Freshly isolated or cultured cells were subjected to CD4 positive MACSorting and/or stained with the appropriate combination of fluorochrome-conjugated mouse/human antibodies (see Supplemental methods). Cells were analyzed with LSRII Fortessa analyzer. In the respective experiments, T cell fractions were sorted with FACSAria III (purity > 98%). For intracellular protein staining, cardiac fibroblasts were stained with anti-mouse/human αSMA (Sigma) and anti-human collagen I-biotin (Acris) antibodies (see Supplemental methods) and analyzed with LSRII Fortessa analyzer.
Histopathology, immunohistochemistry and immunocytochemistry
Conventional hematoxylin/eosin and Masson’s trichrome staining were used to assess cardiac inflammation and fibrosis, respectively (see Supplemental methods). Immunopositive cells (for CD3, CD45, CD45.1, CD90.1) and fibrotic markers (Masson’s Trichrome; αSMA; periostin, vimentin, both Abcam) were quantified using Olympus BX51 microscope and cellSens (Olympus) or Fiji software. Formalin fixed, paraffin embedded human heart tissue from 10 lymphocytic myocarditis patients were obtained from the Biobank of the Institute for Pathology and Neuropathology, University Hospital Tubingen in accordance with local ethical regulations and stained using rabbit anti-human CD4 (EPR6855, Abcam), mouse anti-human CD45RO (UCHL-1, eBioscience) and mouse anti-human CD45RA (HI100, eBioscience); see Supplemental Methods. Image acquisition was performed with a Zeiss AxioObserver Z1 widefield microscope and processed by ImageJ.
Human and mouse cardiac fibroblasts were stained with anti-mouse/human αSMA antibody and phalloidin (Sigma); see Supplemental methods. Image acquisition was performed with a Leica DM IRE2 microscope equipped with the Nomarski Interference Contrast and the Operetta high-content screening platform (Perkin–Elmer).
Transthoracic echocardiography was performed using a Vevo 2100 system equipped with 30-MHz transducer (VisualSonics). Anesthesia was induced by 5% isoflurane and confirmed by the absence of the withdrawal reflex of one of the hind paws. During echocardiogram acquisition isofluorane was reduced to 1.5–2%. The heart was imaged in the bidimensional (2-D) mode, in the parasternal long-axis, short-axis and apical 4-chamber views. Detailed description is available in the Supplemental methods.
Where relevant, data were analyzed by unpaired, two-tailed Student’s t test, one-way ANOVA followed by the Dunnett’s post hoc test (for normally distributed data), or by Mann–Whitney test (for nonparametric data). Differences were considered statistically significant for p < 0.05. All analyses were performed with GraphPad Prism 6 software and values are expressed as mean with SEM or SD.
For the extensive materials and methods we refer to the Supplemental methods.
CD44hiCD62Llow cells represent the effector subset of CD4+ T cells in EAM
Heart non-specific Teff effectively accumulate in the inflamed myocardium
We adopted this T cell transfer model to study mechanisms of T cell trafficking to the heart. To address the differential role of heart-specific and heart non-specific T cells, we used CD4+ T cells from TCR-M and DO11.10 transgenic mouse strains, which expressed transgenic TCRs on their CD4+ T cells. In TCR-M mice, T cells react exclusively to α-MyHC antigen and these mice develop spontaneous myocarditis . On the other hand, chicken ovalbumin (OVA)-reactive DO11.10+ CD4+ T cells from DO11.10 transgenic mice were used as a source of heart non-specific CD4+ T cells. To obtain Teff for the adoptive transfer experiments, splenic and iLN cells from the respective donors were activated with their respective cognate antigen for 72 h and CD4+ T cells were sorted for experiments. Adoptive transfer of heart non-specific DO11.10+ Teff failed to trigger inflammation (Fig. 2a), but DO11.10+ CD4+ T cells entered to a limited extent non-inflamed cardiac tissue (Fig. 2c). In contrast, heart-reactive TCR-M Teff (which express CD90.1 alloantigen ) efficiently accumulated in the recipient hearts after adoptive transfer, although they induced myocarditis less efficiently than CD45.1+CD4+ T cells obtained from α-MyHC/CFA immunized mice (Fig. 2a).
Next, we co-transferred heart non-specific DO11.10+ Teff together with α-MyHC-re-stimulated CD45.1+ Teff from α-MyHC/CFA immunized mice. In inflamed hearts, we found not only myocarditis-inducing α-MyHC-reactive CD45.1+ Teff, but also a massive accumulation of heart non-specific DO11.10+ Teff (Fig. 2c). The total amount of DO11.10+ Teff was substantially higher in the inflamed hearts compared to the non-inflamed organs 10 days after adoptive transfer (Fig. 2d), demonstrating that the inflammatory response effectively attracted heart non-specific Teff into the heart.
Heart non-specific Teff do not affect myocarditis severity, but protect from post-inflammatory fibrosis and cardiac dysfunction
Bystander activation of Teff suppress myofibroblast phenotype of mouse and human cardiac fibroblasts
The transcriptomic analysis showed that in contrast to heart-specific CD45.1+ CD4+ T cells, unstimulated DO11.10+ Teff expressed low levels of extracellular molecules. In stimulatory condition (+α-MyHC), however, a set of 56 genes encoding extracellular factors became specifically upregulated in heart non-specific DO11.10+ Teff, but not in α-MyHC-reactive CD45.1+ Teff (Fig. 4d). This suggested that antigen-independent stimulation of Teff might trigger production of certain antifibrotic factors. To address this option, we co-cultured DO11.10+ Teff with mouse cardiac fibroblasts in the presence or absence of IL-2, IL-7, IL-15 and IL-21 (further called γc-cytokines). Analysis of profibrotic markers in cardiac fibroblasts showed that DO11.10+ Teff stimulated with γc-cytokines effectively suppressed expression of profibrotic genes Acta2, Col1a1 and Fn1 and reduced formation of αSMA fibers (Supp. Fig. 8).
Observations from animal models have pointed to a critical role of CD4+ T cells and heart-specific autoimmunity in the development of myocarditis and cardiac fibrosis, however, surprisingly little experimental data addressed migration and expansion of autoreactive CD4+ T cells in the EAM model. In α-MyHC/CFA immunized mice, essentially only α-MyHC-reactive T cells could be activated with their antigen and turn into Teff phenotype. Our mouse data confirmed that α-MyHC-reactive Teff cells efficiently expand and accumulate in the inflamed cardiac tissue. Furthermore, we demonstrated Teff phenotype of heart infiltrating CD4+ T cells also in human myocarditis. Animals housed under high hygiene standards lack, however, other antigen-activated Teff cells, which are commonly present in humans due to exposure to various infectious agents. To address migratory properties of heart non-specific Teff, we used a T cell adoptive transfer model of DO11.10+ CD4+ T cells activated in vitro with OVA antigen and found that Teff cardiotropism was not restricted to heart-specific CD4+ T cells. It seems that expression of specific homing molecules, rather than antigen-specificity primary controls migration of CD4+ T cells into the cardiac tissue. In fact, such cardiotropic signature has been recently suggested . In our model, we observed more efficient accumulation of heart-specific CD4+ T cells during the early phase of inflammation, while heart non-specific CD4+ T cells were more prevalent at later phases. This differential kinetics could be the result of differential cell expansion/survival in the periphery and/or differential expression of homing molecules by these two types of CD4+ T cells.
Antigen-specific responses of α-MyHC-reactive CD4+ T cells are crucial for myocarditis induction. Our results pointed to Th1/Th17 skewed antigen-dependent response of heart-specific Teff. On the one hand, Th1 cytokines are considered to be involved in the myocarditis induction at a very early stage . Th17 polarized responses, on the other hand, have been associated with worsened myocarditis outcome due to increased cardiac fibrosis and heart failure in both, EAM and human patients [2, 29, 31]. These data might suggest that myocardial fibrosis and DCM phenotype after α-MyHC/CFA immunization is a direct consequence of the Th1/Th17 polarisation of α-MyHC-reactive CD4+ T cells. Furthermore, adoptive transfer experiments demonstrated that heart-specific CD4+ T cell mediated myocarditis induction paralleled a strong bystander activation of heart non-specific CD4+ T cells. Such antigen-independent expansion of activated Teff has been described in the context of viral infections , in breast cancer  and after vaccination . Insights from other disease models point to various innate stimuli [18, 32] and γc-cytokines [12, 33] as potential mediators. We assume that in myocarditis, mainly γc-cytokines produced by heart-specific CD4+ T cells promote the antigen-independent response of heart non-specific CD4+ T cells.
In our model heart non-specific Teff effectively competed with heart-specific Teff and eventually partially replaced them in the inflamed myocardium at later stages of disease. Our data showed that heart non-specific Teff produced a distinct set of cytokines compared to heart-specific Teff. This is not surprising, considering that heart-specific Teff responded to antigen (α-MyHC), while heart non-specific Teff showed antigen-independent response only. Interestingly, heart non-specific Teff expressed high levels of pro-inflammatory cytokines, such as Tnf, Lta or Mif. This result could explain why heart non-specific Teff did not affect the severity of the acute cardiac inflammatory response.
In contrast, adoptive transfer of heart non-specific Teff successfully prevented development of post-inflammatory fibrosis in the EAM model. We found that bystander activation of the heart non-specific Teff induced production of surprisingly high number of extracellular molecules. Some of these factors might be antifibrotic and thus actively inhibit fibrotic processes. Sfrp2 represents an example of such antifibrotic agent, which was specifically expressed by activated heart non-specific Teff. We have recently demonstrated that systemic administration of sFRP2 during acute phase of myocarditis prevented development of fibrotic changes in the EAM model by blocking profibrotic Wnt signalling . The in vitro data have also pointed to the secretion of antifibrotic factors by mouse and human Teff activated in antigen-independent manner. Furthermore, heart non-specific Teff by replacing heart-specific Teff could reduce cardiac levels of profibrotic cytokines, such as IL-17A, in the inflamed heart. We consider these two mechanisms being responsible for antifibrotic effect of the heart non-specific Teff (Supp. Fig. 11). Noteworthy, the analysis of cytokine and extracellular factors production by heart-specific and heart non-specific Teff was performed on restimulated splenic cells only. Lack of data obtained from the heart-infiltrating Teff is a major limitation of this study. We did not perform such analysis due to technical difficulties.
Cardiac fibrosis is a key driver of DCM . Accordingly, in the EAM model, development of cardiac fibrosis was associated with impaired cardiac function and increased heart size . Our data confirmed that function of fibrotic heart are significantly compromised in the α-MyHC/CFA EAM model (ejection fraction reduced from 58% before immunisation to 40% at d40). It is, therefore, not surprising that antifibrotic effect of heart non-specific Teff protected cardiac function and development of DCM phenotype. It should be noted that interplay between cardiac inflammation and fibrosis is of high relevance, not only in myocarditis, but also in other heart diseases . These results further stress the importance of antifibrotic therapies for the positive outcome of myocarditis. A number of antifibrotic agents successfully prevented development of DCM phenotype in animal models [4, 5, 20, 25].
In contrast to the EAM model, heart-specific T cells are usually not the primary inducers of myocarditis in humans [7, 22]. Instead, viruses and parasites represent the most common triggers of lymphocytic infiltration in the myocardium and heart-specific autoimmunity is predominantly associated with the disease progression [3, 8]. By shedding light on the importance of antigen-independent responses, our data provide a link between insights from animal models and observations in humans. Accordingly, our findings can potentially explain the difficulties in identifying heart-specific CD4+ T cells in human myocarditis. We suggest that inflammation-driven, antigen-independent migration and proliferation of Teff could account for extensive cardiac accumulation of heart non-specific CD4+ T cells. So far, there are no concrete data on the numbers of heart-reactive CD4+ T cells in human myocarditis, but considering that heart-specific CD4+ T cells are rather infrequent in humans, we hypothesize that a significant proportion of heart-infiltrating CD4+ T cells in myocarditis patients do not react against cardiac antigens. From this point of view, and given the antifibrotic and cardioprotective properties of heart non-specific Teff, significant infiltrations with CD4+ T lymphocytes could even indicate favourable outcome in myocarditis. Indeed, most patients with lymphocytic myocarditis recover, while only some develop DCM phenotype [11, 28]. The observation that chronic inflammation and long-term antigen activation alters Teff responses  supports our idea that a bystander activation of CD4+ T cell protects myocarditis patients from progression to heart failure.
So far, investigations addressing the role of CD4+ T cells in myocarditis focused on heart-specific autoimmunity. Our data underline potential importance of antigen-independent CD4+ T cell responses in the progression from myocarditis to DCM and attribute them a cardioprotective role. Individual differences in the capability of the immune system to express such functions could explain variable clinical outcomes of lymphocytic myocarditis. The relevance of our findings has to be validated in human patients, since EAM model only partially mimics the complexity of naturally occurring myocarditis. At the same time, further research is needed to elucidate molecular mechanisms and to enable translation of these findings into appropriate therapeutic approaches.
Martina Zarak-Crnkovic acknowledges the support from the Integrative Molecular Medicine PhD program. The authors acknowledge the assistance and support of the Center for Microscopy and Image Analysis and the Flow Cytometry Facility of the University of Zurich, as well as the Functional Genomics Center Zurich.
Research grants from the GZO Regional Health Center, Swiss National Foundation 310030_149785, Hartmann-Mueller Foundation, Swiss Life Jubiläumsstiftung, Olga Mayenfisch Foundation, Swiss Heart Foundation.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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