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Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging

Lookup NU author(s): Professor Ioakim Spyridopoulos

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.


Publication metadata

Author(s): Delgobo M, Heinrichs M, Hapke N, Ashour D, Appel M, Srivastava M, Heckel T, Spyridopoulos I, Hofmann U, Frantz S, Ramos GC

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2021

Volume: 12

Online publication date: 19/02/2021

Acceptance date: 04/01/2021

Date deposited: 04/11/2021

ISSN (electronic): 1664-3224

Publisher: Frontiers Media SA

URL: https://doi.org/10.3389/fimmu.2021.584538

DOI: 10.3389/fimmu.2021.584538

PubMed id: 33679735


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