Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma
Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma
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DOI：
10.1182/blood-2005-08-3376
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发表时间：
2006-05-01
期刊：
影响因子：
20.3
通讯作者：
Ansell, SM
中科院分区：
文献类型：
--
作者：
Yang, ZZ;Novak, AJ;Ansell, SM
大多数非霍奇金淋巴瘤（NHL）是B细胞起源的，但肿瘤组织可以被T细胞浸润。在本研究中，我们已经确定了一个CD 4（+）CD 25（+）T细胞亚群，具有高水平的CTLA-4和Foxp 3（肿瘤内T-reg细胞），在B细胞NHL的活检标本中过度表达（淋巴瘤活检标本中中位数为17%，炎性扁桃体为12%，无肿瘤淋巴结为6%; P = 0.001）。我们发现这些CD 4（+）CD 25（+）T细胞抑制了PHA刺激下浸润的CD 4（+）CD 25（-）T细胞的增殖和细胞因子（IFN-γ和IL-4）的产生。PD-1在浸润性CD 4（+）CD 25（-）T细胞亚群上组成性表达，B7-H1在B细胞NHL中可在瘤内CD 4（+）CD 25（+）T细胞上诱导表达。抗B7-H1抗体或PD-1融合蛋白与肿瘤内T-reg细胞共培养时，可部分恢复浸润的CD 4（+）CD 25（-）细胞的增殖。最后，我们发现淋巴瘤B细胞分泌的CCL 22参与表达CCR 4但不表达CCR 8的肿瘤内T-reg细胞的趋化和迁移。综上所述，我们的结果表明，Treg细胞在B细胞NHL的区域中高度代表，并且恶性B细胞参与了这些细胞向淋巴瘤区域的募集。
Most non-Hodgkin lymphomas (NHLs) are of B-cell origin, but the tumor tissue can be variably infiltrated with T cells. In the present study, we have identified a subset of CD4(+)CD25(+) T cells with high levels of CTLA-4 and Foxp3 (intratumoral T-reg cells) that are overrepresented in biopsy specimens of B-cell NHL (median of 17% in lymphoma biopsies, 12% in inflammatory tonsil, and 6% in tumor-free lymph nodes; P = .001). We found that these CD4(+)CD25(+) T cells suppressed the proliferation and cytokine (IFN-gamma and IL-4) production of infiltrating CD4(+)CD25(-) T cells in response to PHA stimulation. PD-1 was found to be constitutively and exclusively expressed on a subset of infiltrating CD4(+)CD25(-) T cells, and B7-H1 could be induced on intratumoral CD4(+)CD25(+) T cells in B-cell NHL. Anti-B7-H1 antibody or PD-1 fusion protein partly restored the proliferation of infiltrating CD4(+)CD25(-) cells when cocultured with intratumoral T-reg cells. Finally, we found that CCL22 secreted by lymphoma B cells is involved in the chemotaxis and migration of intratumoral T-reg cells that express CCR4, but not CCR8. Taken together, our results suggest that Treg cells are highly represented in the area of B-cell NHL and that malignant B cells are involved in the recruitment of these cells into the area of lymphoma.