Adaptive Immunity Lab

The challenge

The role of T cells in cardiovascular and metabolic diseases

Cardiovascular and metabolic diseases are a major cause of morbidity and mortality. Several forms of cardiac pathology are in urgent need of clinical solutions.
The evolution of adaptive immunity may have been shaped by the evolution of mammalian pregnancy – as pregnancy requires active tolerance by the maternal adaptive immunity of paternally-derived antigens. This leads to an immune system that may optimized for the reproductive age of the female but not beyond. As a consequence, adaptive immunity and inflammation may play key but mal-adapted roles in cardiovascular and metabolic diseases – diseases tightly linked to aging (PMID: 32296427). Unraveling the role of adaptive immunity in cardiovascular disease, down to the cellular and molecular level, including identifying the specific triggers of these adaptive responses, could lead to new therapeutic and diagnostic/prognostic strategies for cardiovascular and metabolic disease, as well for the cardiac side-effects of tumor immunotherapy.

Research areas

Adaptive immunity in Cardiovascular Disease

A few years ago we identified, via immunophenotyping, an association between the presence of pro-inflammatory T cells in cardiac tissue and heart failure progression. On the basis of these findings, we used an FDA-approved drug that interferes with T cell function (T cell costimulation inhibitor) in order to treat different forms of heart failure in mice, successfully hindering disease progression (PMIDs: 28262700, 32806992). This protocol has since been successfully used in human oncology patients suffering from tumor immunotherapy-induced cardiotoxicity (PMIDs: 31189043, 33257470, 36815259), and even entered the ASCO/ESMO guidelines for treatment of tumor immunotherapy-induced cardiotoxicity.

In parallel, we have also developed therapies manipulating adaptive immunity for therapeutic purposes for vascular disease (PMID: 32931583). We are currently developing several, more advanced strategies for the therapeutic manipulation of adaptive immunity in cardiac disease.

To unravel more mechanistic details, we performed the first ever single-cell RNASeq mapping of the cardiac immune infiltrate in Heart Failure (PMID: 31661975). The results offered novel mechanistic explanations for several clinical observations, validating the hypothesis that manipulation of adaptive immunity may hold great potential for clinical benefit in cardiovascular disease.

Adaptive immune cells act in an antigen-specific manner, and knowledge of their antigen specificity can enable far more precise diagnostic and therapeutic applications. In the last few years we have initiated a second-generation set of studies, with a focus on identifying the antigens that drive cardiac disease. We have developed an innovative pipeline for the identification of the antigens driving these pathogenic adaptive immune responses; and we have used it to identify the antigens involved in the responses that mediate different forms of cardiovascular disease.

We have thus uncovered that Long-COVID-19 patients with cardiac symptoms share autoimmune adaptive responses against heart auto-antigens (PMID: 37549204). In a key mechanistic advance, we showed that these responses, when re-created, were sufficient to generate cardiac pathology, demonstrating their causal role in disease. Their triggering mechanism, based on bystander activation, may also explain the diversity of Long-COVID symptoms.

We applied the antigen discovery pipeline to non-ischemic Heart Failure in mice and humans, identifying novel cardiac autoantigens. We used these to demonstrate that pressure overload-driven Heart Failure fulfills the classical conditions used to define autoimmune disease: transfer of lymphocytes or serum is sufficient to transfer disease from cardiopathic to healthy mouse recipients, self-antigens exist that can induce the disease when used in immunization, and HF patients have memory T cells that have already recognized these antigens. We then used the discovered antigens in a tolerogenic formulation to preventively reduce the severity of symptoms of Heart Failure, by inducing antigen-specific immunosuppressive Treg, effectively functioning as a Heart Failure tolerizing vaccine. These findings suggest that HF features an autoimmune-like mechanism in its progression. They also provide a proof-of-concept for antigen-specific immunotherapy for cardiac disease. This study was published recently PMID: 39629560 and was featured on the cover of Circulation Research.

Our immunophenotyping efforts are currently extending in the deep immuno-cardio-characterization of extensive cohorts of human cardiac disease patients. This analysis includes innovative aspects of deciphering the antigen specificity of the T cell responses driving disease. These efforts are likely to yield novel prognostic/diagnostic tools, as well as strengthen the case for the translational relevance of cardio-immunotherapy.

Adaptive immunity and Cardiovascular Disease in the female, in the context of pregnancy

Our past work has revealed how the physiology of reproduction in the female mammal may be a crucial driver for the evolution of regulation of adaptive immunity (PMIDs: 14758358, 17197426, 17440618, 22004905, 32296427). A corollary is that the centrality of reproduction in mammals offers a powerful key to unravel how immunity functions; by extension, this will affect the incidence and progression of cardiovascular disease. The lab has several ongoing projects examining aspects of this question.