Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease
Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease
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DOI：
10.1182/blood-2008-06-165506
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发表时间：
2009-04-30
期刊：
影响因子：
20.3
通讯作者：
Strober, Samuel
中科院分区：
文献类型：
--
作者：
Pillai, Asha B.;George, Tracy I.;Strober, Samuel
尽管CD 4（+）CD 25（+）T细胞（T调节细胞[TlR]）和自然杀伤T细胞（NKT细胞）各自保护免受移植物抗宿主病（GVHD），但这两种调节细胞群体在异基因骨髓移植（BMT）后的相互作用尚未研究。我们发现，宿主NKT细胞可以诱导供体Tlymphocyte的体内扩增，从而防止小鼠在接受分次淋巴照射（TLI）和抗T细胞抗体（TLI和抗胸腺细胞球蛋白（ATG），然后进行异基因造血细胞移植（HCT））后发生致死性GVHD，这是一种模拟人类GVHD保护性非清髓性方案的方案。在NKT细胞缺陷的J α 18（-/-）宿主和白细胞介素-4（IL-4）（-/-）宿主中，或当供体移植物是Treg耗尽时，GVHD保护丧失。供体T细胞或野生型宿主NKT细胞的加回恢复了GVHD保护。供体Treg增殖在IL-4（-/-）宿主中或当IL-4（-/-）小鼠用作过继转移的NKT细胞来源时丧失，表明TLI/抗胸腺细胞血清后供体Treg增殖的宿主NKT细胞增强是IL-4依赖性的。我们的研究结果表明，宿主NKT细胞和供体T细胞可以在BMT后协同作用，并提供了一种机制，通过该机制，旨在保护宿主调节细胞的策略可以增加体内供体Treg扩增，以调节同种异体HCT后的GVHD。（血。2009; 113：4458-4467）
Although CD4(+)CD25(+) T cells (T regulatory cells [Tregs]) and natural killer T cells (NKT cells) each protect against graft-versus-host disease (GVHD), interactions between these 2 regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti-T-cell antibodies, a regimen that models human GVHD-protective nonmyeloablative protocols using TLI and antithymocyte globulin (ATG), followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT-cell-deficient J alpha 18(-/-) hosts and interleukin-4 (IL-4)(-/-) hosts, or when the donor transplant was Treg depleted. Add-back of donor Tregs or wildtype host NKT cells restored GVHD protection. Donor Treg proliferation was lost in IL-4(-/-) hosts or when IL-4(-/-) mice were used as the source of NKT cells for adoptive transfer, indicating that host NKT cell augmentation of donor Treg proliferation after TLI/antithymocyte serum is IL-4 dependent. Our results demonstrate that host NKT cells and donor Tregs can act synergistically after BMT, and provide a mechanism by which strategies designed to preserve host regulatory cells can augment in vivo donor Treg expansion to regulate GVHD after allogeneic HCT. (Blood. 2009; 113: 4458-4467)