Messaoudi Ilhem, Lemaoult Joël, Guevara-Patino Jose A, Metzner Beatrix M, Nikolich-Zugich Janko
Vaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, 505 NW 185th Ave., Beaverton, OR 97006, USA.
J Exp Med. 2004 Nov 15;200(10):1347-58. doi: 10.1084/jem.20040437.
Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8+ T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results in reduced CD8+, but not CD4+, T cell diversity, and in functional inability to mobilize parts of the CD8+ T cell repertoire affected by TCE. In the model of herpes simplex virus (HSV)-1 infection of B6 mice, >90% of the responding CD8+ T cells use Vbeta10 or Vbeta8 and are directed against a single glycoprotein B (gB498-505) epitope, gB-8p. We found that old animals bearing CD8+ TCE within Vbeta10 or Vbeta8 families failed to mount an effective immune response against HSV-1, as judged by reduced numbers of peptide-major histocompatibility complex tetramer+ CD8 T cells and an absence of antiviral lytic function. Furthermore, Vbeta8 TCE experimentally introduced into young mice resulted in lower resistance to viral challenge, whereas Vbeta5+ TCE induced in a similar fashion did not impact viral resistance. These results demonstrate that age-related TCE functionally impair the efficacy of antiviral CD8+ T cell immunity in an antigen-specific manner, strongly suggesting that TCE are not the mere manifestation of, but are also a contributing factor to, the immunodeficiency of senescence.
外周T细胞多样性在年轻个体中基本保持恒定，但在老年小鼠和人类中总是会降低。CD8⁺ T细胞克隆性扩增（TCE）是这种多样性降低的最显著表现，并且可能是其促成因素。我们发现，TCE的存在导致CD8⁺ T细胞多样性降低，但不影响CD4⁺ T细胞多样性，并且在功能上无法调动受TCE影响的部分CD8⁺ T细胞库。在B6小鼠单纯疱疹病毒（HSV）-1感染模型中，>90%的反应性CD8⁺ T细胞使用Vβ10或Vβ8，并针对单个糖蛋白B（gB498-505）表位gB-8p。我们发现，在Vβ10或Vβ8家族中带有CD8⁺ TCE的老年动物无法对HSV-1产生有效的免疫反应，从肽-主要组织相容性复合体四聚体⁺ CD8 T细胞数量减少以及缺乏抗病毒裂解功能可以判断。此外，实验性地将Vβ8 TCE引入年轻小鼠会导致对病毒攻击耐受性降低，而以类似方式诱导的Vβ5⁺ TCE则不会影响病毒抗性。这些结果表明，与年龄相关的TCE以抗原特异性方式在功能上损害抗病毒CD8⁺ T细胞免疫的功效，强烈提示TCE不仅是衰老免疫缺陷的表现，也是其促成因素。
