Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging

• Published in: Frontiers in immunology Vol. 12; p. 584538
• Main Authors: Delgobo, Murilo, Heinrichs, Margarete, Hapke, Nils, Ashour, DiyaaElDin, Appel, Marc, Srivastava, Mugdha, Heckel, Tobias, Spyridopoulos, Ioakim, Hofmann, Ulrich, Frantz, Stefan, Ramos, Gustavo Campos
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 19.02.2021
• Subjects: Aging - genetics; Aging - immunology; Animals; CD4+ T-cells; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells, Cultured; Gene Expression - immunology; Heart Diseases - genetics; Heart Diseases - immunology; Heart Diseases - metabolism; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; HLA-DRB1 Chains - metabolism; Humans; Immunologic Memory - genetics; Immunologic Memory - immunology; Immunology; immunosenescence; inflammaging; lymphocytes; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; myocardial aging; Myocardium - immunology; NSG animals; RNA-Seq - methods; Transplantation, Heterologous; myocardial aging; immunosenescence; inflammaging; NSG animals; lymphocytes; CD4+ T-cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.584538

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.