Brenchley Jason M, Karandikar Nitin J, Betts Michael R, Ambrozak David R, Hill Brenna J, Crotty Laura E, Casazza Joseph P, Kuruppu Janaki, Migueles Stephen A, Connors Mark, Roederer Mario, Douek Daniel C, Koup Richard A
Vaccine Research Center and the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Blood. 2003 Apr 1;101(7):2711-20. doi: 10.1182/blood-2002-07-2103. Epub 2002 Nov 14.
Virus-specific CD8(+) T-cell responses play a pivotal role in limiting viral replication. Alterations in these responses, such as decreased cytolytic function, inappropriate maturation, and limited proliferative ability could reduce their ability to control viral replication. Here, we report on the capacity of HIV-specific CD8(+) T cells to secrete cytokines and proliferate in response to HIV antigen stimulation. We find that a large proportion of HIV-specific CD8(+) T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture. This lack of proliferative ability of HIV-specific CD8(+) T cells is defined by surface expression of CD57 but not by absence of CD28 or CCR7. This inability to proliferate in response to antigen cannot be overcome by exogenous interleukin-2 (IL-2) or IL-15. Furthermore, CD57 expression on CD8(+) T cells, CD4(+) T cells, and NK cells is a general marker of proliferative inability, a history of more cell divisions, and short telomeres. We suggest, therefore, that the increase in CD57(+) HIV-specific CD8(+) T cells results from chronic antigen stimulation that is a hallmark of HIV infection. Thus, our studies define a phenotype associated with replicative senescence in HIV-specific CD8(+) T cells, which may have broad implications to other conditions associated with chronic antigenic stimulation.
病毒特异性CD8(+) T细胞反应在限制病毒复制中起关键作用。这些反应的改变，如细胞溶解功能降低、成熟异常和增殖能力受限，可能会降低它们控制病毒复制的能力。在此，我们报告了HIV特异性CD8(+) T细胞在响应HIV抗原刺激时分泌细胞因子和增殖的能力。我们发现，很大一部分在响应同源抗原时产生细胞因子的HIV特异性CD8(+) T细胞在48小时的体外培养过程中无法分裂并死亡。HIV特异性CD8(+) T细胞这种增殖能力的缺乏是由CD57的表面表达所定义的，而不是由CD28或CCR7的缺失所定义的。这种对抗原刺激无法增殖的情况不能通过外源性白细胞介素-2（IL-2）或IL-15来克服。此外，CD8(+) T细胞、CD4(+) T细胞和NK细胞上的CD57表达是增殖无能、更多细胞分裂历史和短端粒的一个普遍标志。因此，我们认为，CD57(+) HIV特异性CD8(+) T细胞的增加是由慢性抗原刺激导致的，这是HIV感染的一个标志。因此，我们的研究定义了一种与HIV特异性CD8(+) T细胞复制性衰老相关的表型，这可能对与慢性抗原刺激相关的其他情况具有广泛影响。
