DataSheet_1_Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging.docx

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.

心血管与免疫系统随着年龄的增长而发生深刻的、错综复杂的改变。近期研究报道，老年受试者体内记忆细胞和终末分化的T细胞的积累可能加剧心肌老化并促进心脏疾病的发展。尽管如此，免疫衰老谱系是否足以引起与年龄相关的心脏退化，或者仅仅作为先前组织内在损伤的放大器，仍未得到明确。本研究旨在通过研究携带衰老样扩大的CD4+ T细胞区室的幼鼠，来分解这一心免疫交互作用中的因果关系。因此，表达HLA-DRB1*01:01的免疫缺陷型NSG-DR1小鼠被移植了从匹配供体中纯化的CD4+ T细胞，这些细胞在受体内迅速定植并扩增，而不会引起异种移植反应。在供体中，CD4+ T细胞区室主要由定义为CCR7+CD45RO-的原始细胞组成。然而，当移植到年轻的淋巴细胞缺陷型小鼠中时，CD4+ T细胞经历了稳态扩增，PD-1受体的表达上调，并强烈地向效应/记忆（CCR7-CD45RO+）和终末分化表型（CCR7-CD45RO-）转变，这在老年人中是典型的。分化的CD4+ T细胞也在受体的心肌中浸润，其水平与生理性老化观察到的水平相当。此外，携带扩大的CD4+ T细胞区室的幼鼠在心脏中显示出浸润的单核细胞、巨噬细胞和树突状细胞的数量增加。大量mRNA测序分析进一步证实，扩增的T细胞促进心肌的炎症性老化，这表现为独特的与年龄相关的转录组特征。总之，这些数据表明，CD4+ T细胞过度扩增和分化，这是老化免疫系统的特征之一，足以在幼年健康小鼠中促进与炎症性老化相符合的心肌改变。