Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD
Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD
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DOI：
10.1182/blood-2015-10-672345
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发表时间：
2016-02-04
期刊：
影响因子：
20.3
通讯作者：
Ritz, Jerome
中科院分区：
文献类型：
--
作者：
Alho, Ana C.;Kim, Haesook T.;Ritz, Jerome
异基因造血干细胞移植（HSCT）后免疫耐受的形成和维持需要供体来源的CD 4调节性T细胞（CD 4 Tcons）以及效应CD 4（常规CD 4 T细胞[CD 4 Tcons]）和CD 8 T细胞的平衡重建。为了描述导致这些不同T细胞群体不平衡恢复的复杂机制，我们研究了107名在降低强度条件反射后接受T-充满干细胞移植的成年患者。监测CD 4 Treg、CD 4 Tcon和CD 8 T细胞的免疫重建2年。在此期间，CD 3 T细胞计数逐渐恢复到正常水平，但CD 8 T细胞恢复得比CD 4 T细胞或CD 4 Tcons更快。重建的CD 4 T细胞和CD 4 T细胞主要是中央记忆（CM）和效应记忆（EM）细胞，并且CD 8 T细胞主要是末端EM细胞。在2年研究期间，维持了胸腺产生的初始CD 4 Tcon和CD 8 T细胞，但胸腺产生的CD 4 Tcon显著降低，几乎没有恢复。T细胞增殖倾向于CM和EM CD 4 Tcon和CD 8 T细胞，特别是HSCT后6至12个月。在HSCT后的前3至6个月，CD 4 Tcon和CD 8 T细胞中BCL 2的细胞内表达增加。移植后3个月，每个T细胞群中幼稚和CM组分的早期恢复也与随后慢性移植物抗宿主病（GVHD）的发生密切相关。这些动态失衡有利于效应T细胞的产生、扩增和持续，而不是CD 4 T细胞，并与慢性GVHD的发展相关。
The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4 Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD.