Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.
Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.
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DOI：
10.1371/journal.pone.0013623
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发表时间：
2010-10-26
期刊：
影响因子：
3.7
通讯作者：
Kraj P
中科院分区：
文献类型：
--
作者：
Kuczma M;Kopij M;Pawlikowska I;Wang CY;Rempala GA;Kraj P
肿瘤病变中Foxp 3+调节性CD 4 + T细胞的存在被认为是癌症中免疫应答无效的主要原因之一。尚不清楚肿瘤内Treg细胞是否代表预先存在于健康小鼠中的Treg细胞，或来自肿瘤特异性效应CD 4 + T细胞并因此代表适应性Treg细胞。最近的证据表明，在人和小鼠中，Treg细胞的外周群体是异质的，并且由可能对肿瘤来源的抗原有差异反应的亚群组成，这可能使肿瘤中Treg群体的产生进一步复杂化。我们研究了实验小鼠癌症中的Treg细胞，这些细胞表达天然选择的CD 4 + T细胞多克隆库，并且保留了Treg群体的异质性。健康小鼠中存在的大多数Treg细胞保持稳定的抑制表型，表达高水平的Foxp 3和未被初始CD 4 + T细胞使用的一组排他性TCR。小Treg亚群利用与效应T细胞共享的TCR，并表达较低水平的Foxp 3。我们表明，对肿瘤衍生抗原的反应诱导了抗原特异性效应细胞和Treg细胞的有效克隆募集和扩增。然而，肿瘤中的Treg细胞群由表达与效应CD 4 + T细胞共有的TCR的细胞占主导地位。相比之下，在健康小鼠中占主导地位的表达一组独特TCR的Treg细胞仅占肿瘤病变中所有Treg细胞的一小部分。我们的研究结果表明，肿瘤中的Treg库是由效应CD 4 + T细胞的转化或Treg细胞的小亚群的扩增产生的。总之，成功的癌症免疫治疗可能取决于阻断效应CD 4 + T细胞中Foxp 3上调和/或选择性抑制次要Treg亚群扩增的能力。
The presence of Foxp3+ regulatory CD4+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral Treg cells represent Treg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4+ T cells and thus representing adaptive Treg cells. The generation of Treg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of Treg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied Treg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4+ T cells and which preserve the heterogeneity of the Treg population. The majority of Treg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4+ T cells. A small Treg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and Treg cells. However, the population of Treg cells in tumors was dominated by cells expressing TCRs shared with effector CD4+ T cells. In contrast, Treg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all Treg cells in tumor lesions. Our results suggest that the Treg repertoire in tumors is generated by conversion of effector CD4+ T cells or expansion of a minor subset of Treg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4+ T cells and/or selectively inhibiting the expansion of a minor Treg subset.
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影响因子：
11.2
作者：
Lehe, Cynthia;Ghebeh, Hazem;Dermime, Said
通讯作者：
Dermime, Said
影响因子：
--
作者：
KULLBACK, S;LEIBLER, RA
通讯作者：
LEIBLER, RA
DOI：
10.1073/pnas.222463499
发表时间：
2002-11-12
影响因子：
11.1
作者：
Chmielowski, B;Pacholczyk, R;Ignatowicz, L
通讯作者：
Ignatowicz, L
DOI：
10.1073/pnas.0811556106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Komatsu, Noriko;Mariotti-Ferrandiz, Maria Encarnita;Hori, Shohei
通讯作者：
Hori, Shohei
DOI：
10.4049/jimmunol.0802535
发表时间：
2009-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Haribhai D;Lin W;Edwards B;Ziegelbauer J;Salzman NH;Carlson MR;Li SH;Simpson PM;Chatila TA;Williams CB
通讯作者：
Williams CB