Human CD4+CD25hiFoxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo
Human CD4+CD25hiFoxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo
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DOI：
10.1172/jci28941
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Akbar, Arne N.
中科院分区：
文献类型：
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作者：
Vukmanovic-Stejic, Milica;Zhang, Yan;Akbar, Arne N.
虽然记忆 T 细胞通过持续更新来维持，但人类调节性 CD4(+)CD45RO(+)CD25(hi) Foxp3(+) T 淋巴细胞群如何在整个生命过程中持续存在尚不清楚。因此，我们使用体内循环细胞的氘标记来确定这些细胞是否可以通过增殖来补充。我们发现，与记忆 CD4(+)CD45RO(+)Foxp3(-)CD25(-)（24 天）或初始 CD4(+)CD45RA(+)Foxp3(-)CD25(-) 群体相比，CD4(+)CD45RO(+)Foxp3(+)CD25(hi) T 淋巴细胞高度增殖，倍增时间为 8 天 (199天）。然而，调节群体容易发生细胞凋亡，并且端粒极短，端粒酶活性低。因此它不太可能自我再生。这些数据与另一个种群来源的连续生产一致。我们发现调节性CD4(+)T细胞和记忆性CD4(+)T细胞之间的TCR克隆同源性极其接近。此外，某些 TCR V beta 家族中抗原相关的扩增与使用相同 V beta 的 CD4(+)CD45RO(+)CD25(hi)Foxp3(+) Tregs 的平行数量增加相关。因此，所有人类 CD4(+)CD25(+)Foxp3(+) Tregs 不太可能在胸腺中作为单独的功能谱系产生。相反，我们的数据表明，这一调节群体的一部分是由快速分裂、高度分化的记忆 CD4(+) T 细胞产生的；这对于体内这些细胞的治疗操作具有相当大的意义。
While memory T cells are maintained by continuous turnover, it is not clear how human regulatory CD4(+)CD45RO(+)CD25(hi) Foxp3(+) T lymphocyte populations persist throughout life. We therefore used deuterium labeling of cycling cells in vivo to determine whether these cells could be replenished by proliferation. We found that CD4(+)CD45RO(+)Foxp3(+)CD25(hi) T lymphocytes were highly proliferative, with a doubling time of 8 days, compared with memory CD4(+)CD45RO(+)Foxp3(-)CD25(-) (24 days) or naive CD4(+)CD45RA(+)Foxp3(-)CD25(-) populations (199 days). However, the regulatory population was susceptible to apoptosis and had critically short telomeres and low telomerase activity. It was therefore unlikely to be self regenerating. These data are consistent with continuous production from another population source. We found extremely close TCR clonal homology between regulatory and memory CD4(+) T cells. Furthermore, antigen-related expansions within certain TCR V beta families were associated with parallel numerical increases of CD4(+)CD45RO(+)CD25(hi)Foxp3(+) Tregs with the same V beta usage. It is therefore unlikely that all human CD4(+)CD25(+)Foxp3(+) Tregs are generated as a separate functional lineage in the thymus. Instead, our data suggest that a proportion of this regulatory population is generated from rapidly dividing, highly differentiated memory CD4(+) T cells; this has considerable implications for the therapeutic manipulation of these cells in vivo.