T Cell Polarization in Heart Failure

Corresponding Author

The adaptive immune system, composed of T and B cells, most likely evolved in vertebrates in response to a need to defend the body from pathogens. Pathogens can belong to different groups (eg, intracellular bacteria and viruses, parasites such as worms, extracellular bacteria), each of which can be best dealt with by using combinations of effector molecules and cells of the immune system (antibodies, cytokines, specialized cells of innate immunity such as macrophages or eosinophils). The detection of the class of pathogen occurs through specialized receptors expressed by innate immune cells; yet, the commitment to the most appropriate response (a process termed polarization) is decided by CD4⁺ T helper (Th) cells, which then guide all other immune cells toward the most suitable response. Each polarization “flavor” features distinct chemokines and chemokine receptors, which help guide the immune cells to where the pathogen may lie. The responses most suited to viruses and intracellular bacteria, termed Th1, feature several chemokine receptors, key among which is CXCR3, and its ligands CXCL9, CXCL10, and CXCL11.¹

Pressure overload (PO)–induced heart failure is not caused by pathogens. Yet, the progression of the pathological phenotype is dependent on the action of CD4⁺ T cells, as a series of studies in the last decade have shown.2, 3, 4 The drivers of these T cells are neoantigens and self-antigens,⁵ yet an immune system evolved for dealing with microbes will nonetheless pick a flavor of polarization, presumably according to how the inflammation generated by the effect of PO on cardiac tissues is interpreted by the immune system. Previous work has shown a clear Th1-like polarization in PO-induced heart failure, involving cytokine IFNγ and chemokine receptor CXCR3.^6,7

In this issue of JACC: Basic to Translational Science, Souza-Neto et al⁸ identify that CXCL10, one of the chemokine ligands of CXCR3, is up-regulated in cardiac macrophages during PO. This finding is highly consistent with the previously identified roles for Th1-like polarization in PO-induced heart failure. In a crucial, and convincing, experiment, the authors induced PO in mice genetically deficient of CXCL10. Intriguingly, they found that, in the short term, 1 week postinduction of the PO, absence of CXCL10 led to significant dampening of the hypertrophy and fibrosis that is normally induced by PO in wild-type animals.

More importantly, by 6 weeks postinduction, absence of CXCL10 led to substantial protection not only from hypertrophy and fibrosis, but also from loss of systolic function. This finding suggests that, even if CXCL10 is only one of the possible chemokine ligands of CXCR3, it is necessary for the mediation of a substantial part of the PO-driven phenotype.

As expected, given the T cell–recruiting role of the chemokine, CXCL10 deficiency led to a reduction in CD4⁺ Th1 cells. Given their identification of macrophages as the main source of the chemokine, the authors further attempted to revert the phenotype in CXCL10-deficient, PO-treated mice by adoptively transferring bone marrow cells, from where the monocyte-derived cardiac macrophages emerge. Indeed, CXCL10-sufficient bone marrow reversed the protective effect of CXCL10 deficiency in cardiac hypertrophy, albeit without affecting other parameters such as fibrosis.

Collectively, the data presented by Souza-Neto et al offer solid evidence in further support of a Th1-like polarization in PO-induced heart failure. It is noteworthy that similar polarization has also been observed in other forms of cardiac disease, such as age-driven cardiac dysfunction⁹ and tumor immunotherapy–induced myocarditis.¹⁰ The findings open up new avenues of translational research, as targeting these common immunological pathways may hold potential for benefit for more than one cardiac ailment. A challenge, at the same time, will be how to modulate these pathways, which are—by evolution—useful for the defense from pathogens, in a way that dampens the cardiotoxicity without opening the door to opportunistic infections. Yet challenges drive innovation, and our understanding of cardioimmunology stands only to gain in the process.

Funding Support and Author Disclosures

Dr Kallikourdis is supported by AIRC.