Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging

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.

CITEMO XMBD : A flexible single-cell multimodal omics analysis framework to reveal the heterogeneity of immune cells

“…CITEMO multimodal omics identifies naive CD4 T cells and memory CD4 T cells from the CD4 T cells according to the abundance of CD45RA ADT ( Fig. 2G and Supplementary Figure 1A) [ 49 , 50 ]. The CITEMO ADT also identifies two CD4 T cell subtypes, i.e.…”

Effects of RAGE Deletion on the Cardiac Transcriptome during Aging

“…CD4(+) T cells participate in cardiac healing after myocardial infarction but can also aggravate heart failure induced by pressure overload [ 28 , 32 , 33 ]. Old CD4(+) T-cell-deficient mice exhibit attenuated cardiac inflammation and dysfunction but similar levels of fibrosis compared to WT mice of the same age [ 29 , 34 ]. Senescent T cells are more pro-inflammatory and, when injected into young lymphocyte-deficient mice, show higher cardiac tropism than young T cells; however, they are not sufficient to cause major functional and structural cardiac alterations [ 29 , 34 ].…”

Immunosenescence in atherosclerosis: A role for chronic viral infections

“…It has been found that IFN-γ-producing CD28 null CD4 + T cells accumulate in the heart-draining lymph nodes of aged mice and adoptive transfer of these cells results in proinflammatory responses in young mice ( 105 , 106 ). It is also shown that senescent CD4 + T cells can infiltrate to heart and promote myocardial inflammation and stress response leading to age-related cardiac dysfunction ( 107 ). Additionally, the importance of senescent T cells has been reported in human hypertension.…”