Recipient myeloid-derived immunomodulatory cells induce PD-1 ligand-dependent donor CD4+Foxp3+ regulatory T cell proliferation and donor-recipient immune tolerance after murine nonmyeloablative bone marrow transplantation.
Recipient myeloid-derived immunomodulatory cells induce PD-1 ligand-dependent donor CD4+Foxp3+ regulatory T cell proliferation and donor-recipient immune tolerance after murine nonmyeloablative bone marrow transplantation.
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DOI：
10.4049/jimmunol.1302191
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发表时间：
2013-12-01
期刊：
影响因子：
--
通讯作者：
Pillai AB
中科院分区：
文献类型：
--
作者：
van der Merwe M;Abdelsamed HA;Seth A;Ong T;Vogel P;Pillai AB
我们之前已经证明，非清髓性总淋巴细胞照射/兔抗胸腺细胞血清（TLI/ATS）调节通过受体不变性自然杀伤T细胞（iNKT细胞）衍生的il -4依赖性扩增供体Foxp3+天然存在的Treg (nTreg)，促进骨髓移植（BMT）后供体-受体免疫耐受，跨越主要组织相容性复合体（MHC）屏障。这里我们报告一个更具体的机制。野生型（WT） BALB/c （H-2d）宿主被给予来自WT或STAT6−/−C57BL/6 （H-2b）供体的TLI/ATS和BMT。STAT6 - / - BMT后，供体nTreg在体内没有增殖损失，表明受体中IL-4应答的群体而不是供体驱动供体nTreg增殖。在GVHD靶器官中，TLI/ATS + BMT与TBI/ATS + BMT相比，三个受体CD11b+细胞亚群（Gr-1highCD11cneg、Gr-1intCD11cneg和Gr-1lowCD11c+）在TLI/ATS + BMT后早期富集。Gr-1lowCD11c+细胞在体外72hr MLR中诱导H-2Kb+CD4+Foxp3+ nTreg增殖。TLI/ATS + BMT后，STAT6−/−和iNKT细胞缺陷的j - α18−/−BALB/c受体中Gr-1lowCD11c+细胞显著减少。CD11b+细胞的消耗导致严重的急性GVHD，将WT Gr-1lowCD11c+细胞过继转移给TLI/ATS + BMT的Jα18−/−BALB/c受体，可以恢复第6天供体Foxp3+ nTreg的增殖和对CD8效应T细胞介导的GVHD的保护。阻断PD-L1或PD-L2，但不阻断CD40、TGF-β、精氨酸酶1或iNOS，可抑制受体来源的Gr-1lowCD11c+细胞与供体nTreg共培养的nTreg增殖。通过inkt依赖性Th2极化，髓源性免疫调节性dc在非清髓性TLI/ATS调节和异基因BMT后扩增，诱导PD-1配体依赖性供体nTreg增殖，并维持强大的移植物抗宿主免疫耐受。
We have previously shown that non-myeloablative total lymphoid irradiation/rabbit anti-thymocyte serum (TLI/ATS) conditioning facilitates potent donor-recipient immune tolerance following bone marrow transplantation (BMT) across major histocompatibility complex (MHC) barriers via recipient invariant natural killer T cell (iNKT cell)-derived IL-4-dependent expansion of donor Foxp3+ naturally occurring Treg (nTreg). Here we report a more specific mechanism. Wild-type (WT) BALB/c (H-2d) hosts were administered TLI/ATS and BMT from WT or STAT6−/− C57BL/6 (H-2b) donors. Donor nTreg following STAT6−/− BMT demonstrated no loss of proliferation in vivo, indicating that an IL-4 responsive population in the recipient rather than the donor drives donor nTreg proliferation. In GVHD target organs, three recipient CD11b+ cell subsets (Gr-1highCD11cneg; Gr-1intCD11cneg; and Gr-1lowCD11c+) were enriched early after TLI/ATS + BMT versus TBI/ATS + BMT. Gr-1lowCD11c+ cells induced potent H-2Kb+CD4+Foxp3+ nTreg proliferation in vitro in 72-hr MLR. Gr-1lowCD11c+ cells were significantly reduced in STAT6−/− and iNKT cell-deficient Jα18−/− BALB/c recipients after TLI/ATS + BMT. Depletion of CD11b+ cells resulted in severe acute GVHD, and adoptive transfer of WT Gr-1lowCD11c+ cells to Jα18−/− BALB/c recipients of TLI/ATS + BMT restored day 6 donor Foxp3+ nTreg proliferation and protection from CD8 effector T cell-mediated GVHD. Blockade of PD-L1 or PD-L2, but not CD40, TGF-β, Arginase 1, or iNOS inhibited nTreg proliferation in co-cultures of recipient-derived Gr-1lowCD11c+ cells with donor nTreg. Through iNKT-dependent Th2 polarization, myeloid-derived immunomodulatory DCs are expanded after non-myeloablative TLI/ATS conditioning and allogeneic BMT, induce PD-1 ligand dependent donor nTreg proliferation, and maintain potent graft-versus-host immune tolerance.
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DOI：
10.1084/jem.20120295
发表时间：
2012-03-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Karp CL;Murray PJ
通讯作者：
Murray PJ
DOI：
10.1186/1756-9966-29-51
发表时间：
2010-05-19
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Huang C;Yang G;Jiang T;Huang K;Cao J;Qiu Z
通讯作者：
Qiu Z
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
158.5
作者：
Lowsky, R;Takahashi, T;Strober, S
通讯作者：
Strober, S
影响因子：
20.3
作者：
Highfill, Steven L.;Rodriguez, Paulo C.;Blazar, Bruce R.
通讯作者：
Blazar, Bruce R.