TY  - JOUR
A1  - Delgobo, Murilo
A1  - Heinrichs, Margarete
A1  - Hapke, Nils
A1  - Ashour, DiyaaElDin
A1  - Appel, Marc
A1  - Srivastava, Mugdha
A1  - Heckel, Tobias
A1  - Spyridopoulos, Ioakim
A1  - Hofmann, Ulrich
A1  - Frantz, Stefan
A1  - Ramos, Gustavo Campos
T1  - Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging
JF  - Frontiers in Immunology
N2  - 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.
KW  - CD4+ T-cells
KW  - myocardial aging
KW  - inflammaging
KW  - NSG animals
KW  - immunosenescence
KW  - lymphocytes
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229612
SN  - 1664-3224
VL  - 12
ER  -