Terminally Differentiated CD4(+) T Cells Promote Myocardial Inflammaging.
Terminally Differentiated CD4(+) T Cells Promote Myocardial Inflammaging.
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终末分化的 CD4(+) T 细胞会促进心肌炎症。
DOI：
10.3389/fimmu.2021.584538
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发表时间：
2021
影响因子：
7.3
通讯作者：
Ramos GC
中科院分区：
文献类型：
--
作者：
Delgobo M;Heinrichs M;Hapke N;Ashour D;Appel M;Srivastava M;Heckel T;Spyridopoulos I;Hofmann U;Frantz S;Ramos GC
心血管系统和免疫系统会随着年龄增长发生深刻且相互交织的变化。近期研究报告称，老年个体中记忆性和终末分化的T细胞积累会加速心肌老化，推动心脏病进展。然而，目前尚不清楚免疫衰老特征是否足以导致与年龄相关的心脏功能恶化，还是仅仅起到放大先前组织内在损伤的作用。在此，我们试图通过研究拥有类似衰老样扩增的CD4 + T细胞区室的年轻小鼠，来剖析这种心脏 - 免疫相互作用中的因果关系。因此，将表达HLA - DRB1 * 01:01的免疫缺陷型NSG - DR1小鼠，移植从匹配供体中纯化的人CD4 + T细胞，这些细胞能在受体小鼠体内快速植入并扩增，且不会引发异种移植反应。在供体个体中，CD4 + T细胞区室主要由定义为CCR7 + CD45RO - 的初始细胞组成。然而，当将其移植到年轻的淋巴细胞缺陷小鼠体内时，CD4 + T细胞会经历稳态扩增，上调程序性死亡受体1（PD - 1）的表达，并强烈向效应/记忆（CCR7 - CD45RO + ）和终末分化表型（CCR7 - CD45RO - ）转变，这在老年人中较为常见。分化的CD4 + T细胞还会以与生理衰老过程中相当的水平浸润受体小鼠的心肌。此外，拥有扩增的CD4 + T细胞区室的年轻小鼠，心脏中浸润的单核细胞、巨噬细胞和树突状细胞数量增加。大量mRNA测序分析进一步证实，扩增的T细胞会促进心肌炎性衰老，其特征为具有明显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（衰老免疫系统的一个标志）足以在幼年健康小鼠中促进与炎性衰老相符的心肌改变。
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.
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影响因子：
5
作者：
Horn MA;Trafford AW
通讯作者：
Trafford AW
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DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
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DOI：
10.12717/dr.2019.23.2.079
发表时间：
2019-06-01
期刊：
Development & reproduction
影响因子：
--
作者：
Lee, Ji Yoon;Han, A-Reum;Lee, Dong Ryul
通讯作者：
Lee, Dong Ryul
影响因子：
4.8
作者：
Brehm, Michael A.;Kenney, Laurie L.;Shultz, Leonard D.
通讯作者：
Shultz, Leonard D.
DOI：
10.1056/nejmoa1701719
发表时间：
2017-07-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jaiswal S;Natarajan P;Silver AJ;Gibson CJ;Bick AG;Shvartz E;McConkey M;Gupta N;Gabriel S;Ardissino D;Baber U;Mehran R;Fuster V;Danesh J;Frossard P;Saleheen D;Melander O;Sukhova GK;Neuberg D;Libby P;Kathiresan S;Ebert BL
通讯作者：
Ebert BL