Immune repertoires in the failing heart: the global picture

This editorial refers to ‘Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization’†, by T.-T. Tang et al., on page 3924. The biology of individual lymphocyte clones and their molecular responses to myocardial injury have been scrutinized over the past few years.1 Different groups reported that CD4+ T cells can foster myocardial repair at earlier stages after myocardial infarction (MI),2 whereas others have shown that they can fuel adverse remodelling in models of ischaemic and hypertrophic heart failure.4–6 The salutary effects of CD4+ T cells has mainly been linked to the subset of regulatory T cells (Tregs) that is defined in mice by expression of the transcription factor Foxp3. Tregs were shown to modulate cardiac fibroblast and macrophage phenotype and function towards promotion of healing. The general view is that resolution of pro-inflammatory activity in the post-infarcted myocardium corresponds to the quality of healing, whereas lack of sufficient inflammation resolution promotes the transition to chronic adverse remodelling. Accordingly, Treg-depleted mice showed pronounced adverse remodelling, decreased survival rates, reduced fractional shortening, and increased left ventricular dilation after MI.3 Conversely, increasing the frequency or activation level of Tregs by different experimental approaches positively impacted healing.3 , 7 Notwithstanding, a recent study found that Tregs exhibit functional perturbations and acquire a pro-inflammatory phenotype in mice with chronic ischaemic heart failure (IHF).5 Moreover, it has been shown that chronic pressure overload stress promotes the activation of interferon-γ-producing T helper cells (Th1) which in turn mediate myocardial fibrosis in mice.4 The solid mechanistic evidence derived from mouse studies indicates that the T-cell response to myocardial injury could be an interesting novel target. However, the very limited availability of human heart tissues and, even more, heart-draining lymph node samples hampered the validation of these results in human patients. Most clinical studies which have been conducted so far were only able to correlate clinical outcome parameters of post-MI or IHF patients with data describing the composition of lymphocyte subsets in the peripheral blood (e.g. Treg, Th1, and Th17). Scientists strive to understand biological processes in as much detail as possible. Nevertheless, from time to time, it is also worth taking a step back and zoom out to catch the global perspective—to avoid ‘not seeing the wood for the trees’. This latter approach can be particularly helpful to cope with T-cell biology and its astonishing clonal diversity. In contrast to most other cell types, each mature CD4+ and CD8+ T cell expresses a unique T-cell receptor (TCR) that is produced through a random somatic recombination of specific gene segments. This generation of diversity process can potentially yield a repertoire of 1015 different TCR clonotypes8 (Figure 1A). Antigen recognition leads to expansion of specific T-cell clones, followed by retraction, while some cells give rise to long-lived memory clones, meaning that the TCR repertoire is in a state of constant change throughout life according to its history of antigenic exposure. Thus, picturing immune repertoires globally, through recently developed high-throughput parallel sequencing tools, offers an exciting opportunity to assess the supra-clonal immunological landscape in a given subject. This approach has been shown to bear diagnostic/prognostic relevance in several infectious and malignant diseases.9 T-cell repertoires in cardiovascular diseases. (A) Antigen recognition by CD4+ T cells and the generation of T-cell receptor (TCR) diversity. The TCR expressed on CD4+ T cells is a heterodimer consisting of α and β chains that recognize peptides presented in the context of major histocompatibility complex molecules. Each T cell bears a unique TCR generated by the somatic rearrangement, and joining of Variable (V, red), Diversity (D, green), and Joining (J, yellow) gene segments. An additional source of TCR diversity comes from nucleotides that can be randomly inserted or deleted at junction sites of rearranged genes (magenta). The potential αβTCR repertoire that can be generated in a mouse is estimated to be ∼1015 unique receptors. High-throughput massive parallel TCR sequencing offers the opportunity to assess the supra-clonal composition of immune repertoires. APC, antigen-presenting cell; MHC-II, major histocompatibility complex-class II. CD8+ T cells undergo similar VDJ rearrangement, but interact with antigens presented in the context of MHC-I. (B) The results of Tang et al. revealed that the cardiac TCR repertoire show signs of oligoclonality (IHF heart > non-failing heart > blood samples). These findings may suggest the existence of a small heart-resident T-cell population, and that clonal expansions of antigen-specific T cells are associated with IHF progression. Servier Medical Art was used to prepare the figure. In the study of Tang et al.10 published in this issue of the European Heart Journal, the authors sought to monitor the T-cell repertoire dynamics in end-stage IHF patients. The authors employed high-throughput parallel TCR sequencing on cardiac and blood samples of IHF patients and multiorgan donors with no cardiac injury. The results revealed that the T-cell compartment found in failing hearts is marked by skewed diversity, clonal expansion, and a unique profile of VDJ rearrangements, as compared with the repertoires seen in peripheral blood or in non-failing hearts, respectively. These clinical observations strongly indicate that clonal expansions of antigen-specific T cells are associated with IHF progression. This notion was further supported by the observation of higher prevalence of some human leucocyte antigen (HLA) alleles in IHF patients, e.g. HLA-A*11:01, HLA-A*11:02 (class-I), and HLA-DQB1*06:02 (class-II). In previous studies, De Palma et al.11 and Klingenberg et al.12 have also shown that patients with acute coronary syndrome show oligoclonal T-cell responses within unstable plaques, and Blohm et al.13 reported a biased usage of TCR variable genes in heart samples obtained from dilative cardiomyopathy patients. The picture emerging from those immune repertoire studies suggests that T-cell autoreactivity to a defined set of autoantigens might be an important factor underlying the development of different cardiovascular diseases. The TCR repertoire analyses performed by Tang et al.10 also revealed important differences between the heart and peripheral blood T-cell compartments, even in the absence of heart failure. In the past few years, several groups have reported that both murine and human hearts harbour resident leucocyte populations, most notably macrophages.14 An early study by Holzinger et al.15 revealed the presence of memory T cells (defined as CD3+CD45RO+) in histological tissue sections of uninjured human hearts obtained from multiorgan donors. The results reported by Tang et al.10 further confirm that healthy human hearts might harbour resident T-cell populations with a distinct reactivity profile. It is therefore reasonable to assume that the cardio-immune cross-talk might precede the onset of diseases, and it may also influence the cardiac physiology processes. Identifying the epitopes targeted by T cells in the failing heart could foster the development of novel diagnostic/prognostic or even therapeutic tools. Unfortunately, it is not currently possible to predict the cognate antigens (peptides presented in the context of major histocompatibility complex molecules) from TCR sequencing data, and the identities of antigens involved in IHF progression are yet to be uncovered. Therefore, the data from Tang et al. cannot answer central questions on antigen specificity such as: what antigens drive T-cell responses in the failing hearts? Are pathogenic T cells reactive to heart-specific antigens or universal injury-associated (neo)-antigens? Studies on experimental autoimmune myocarditis and myocardial infarction have led to the identification of cardiac myosin heavy chain alpha (cardiac isoform) and troponin I as important cardiac antigens in inbred mice.16 , 17 However, it remains unclear whether the same T-cell reactivities would play a role in the clinical setting. Still, based on the data, it is tempting to speculate that either the HLA phenotype or the T-cell receptor repertoire of circulating T cells could bear prognostic potential in chronic heart failure patients. Therefore, the results reported by Tang et al.10 might encourage future prospective studies that link epitope mapping with the clinical outcomes in HF patients. Conflict of interest: G.R., U.H., S.F. report grants from BMBF, during the conduct of the study. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.