Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.
Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.
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DOI：
10.1084/jem.20070567
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发表时间：
2007-09-03
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影响因子：
--
通讯作者：
Picker LJ
中科院分区：
文献类型：
--
作者：
Okoye A;Meier-Schellersheim M;Brenchley JM;Hagen SI;Walker JM;Rohankhedkar M;Lum R;Edgar JB;Planer SL;Legasse A;Sylwester AW;Piatak M Jr;Lifson JD;Maino VC;Sodora DL;Douek DC;Axthelm MK;Grossman Z;Picker LJ
恒河猴的原发性猴免疫缺陷病毒（SIV）感染导致淋巴细胞外效应位点的CD4+ CCR5+效应记忆T （TEM）细胞急剧耗损，但在大多数感染中，CD4+记忆T细胞增殖率的增加似乎可以防止效应位点CD4+ TEM细胞群的崩溃和急性期艾滋病。最终，持续的SIV复制导致慢性艾滋病，但其机制仍有争议。在这里，我们证明了在进行性SIV感染的慢性期，效应位点CD4+ TEM细胞群表现出缓慢、持续的下降，这种下降的程度仍然是迟发性艾滋病的高度显著相关。我们进一步表明，由于持续的免疫激活，效应位点CD4+ TEM细胞主要是短暂的，并且它们的稳态明显依赖于中央记忆T （TCM）细胞前体产生新的CD4+ TEM细胞。随着时间的推移，效应位点CD4+ TEM细胞群的不稳定性并不是由这些细胞的破坏增加来解释的，而是由于CCR5−CD4+ TCM细胞数量的减少导致它们的产量逐渐减少。这些数据表明，尽管CD4+ TEM细胞耗竭是免疫缺陷的一种近似机制，但耗竭的速度和疾病发病的时间在很大程度上取决于CD4+ TCM细胞的破坏、生产失败和逐渐下降。
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector–memory T (TEM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4+ memory T cell proliferation appears to prevent collapse of effector site CD4+ TEM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4+ TEM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central–memory T (TCM) cell precursors. The instability of effector site CD4+ TEM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5− CD4+ TCM cells. These data suggest that although CD4+ TEM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4+ TCM cells.
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