Hombach Andreas A, Abken Hinrich
Department I Internal Medicine, University Hospital Cologne, Cologne D-50931, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, Cologne D-50931, Germany.
Cancers (Basel). 2017 Aug 29;9(9):112. doi: 10.3390/cancers9090112.
Evidences are accumulating that CD4⁺ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4⁺ T cells lyse defined target cells as efficiently as do CD8⁺ T cells. However, the cytolytic capacity of redirected CD4⁺CD25 T cells, in comparison with CD4⁺CD25⁺ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation. We consequently used a CAR with combined CD28-CD3ζ signalling for redirecting CD4⁺CD25 T cells and CD4⁺CD25⁺ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4⁺CD25 CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4⁺CD25 T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4⁺ cells and Treg cells imply their use for different purposes in cell therapy.
越来越多的证据表明，CD4⁺ T细胞可在生理条件下介导抗原特异性靶细胞裂解。通过工程化嵌合抗原受体（CAR）规避主要组织相容性复合体（MHC）限制后，CD4⁺ T细胞裂解特定靶细胞的效率与CD8⁺ T细胞相当。然而，与CD4⁺CD25⁺调节性T（Treg）细胞相比，重定向CD4⁺CD25 T细胞的溶细胞能力迄今尚未得到充分界定。Treg细胞激活需要强CD28信号以及CD3ζ。因此，我们使用具有CD28 - CD3ζ联合信号的CAR来重定向来自同一供体的CD4⁺CD25 T细胞和CD4⁺CD25⁺ Treg细胞。CAR重定向激活这些T细胞亚群，并诱导出独特的细胞因子模式，即Treg细胞释放高IL - 10且缺乏IL - 2释放。尽管有强烈的抗原特异性激活，但CAR Treg细胞仅产生微弱的靶细胞裂解，而CD4⁺CD25 CAR T细胞是有效的杀手。细胞溶解与靶细胞对Fas/FasL介导杀伤的敏感性无关；CAR激活后，CD4⁺CD25 T细胞上调穿孔素和颗粒酶B，而Treg细胞上调程度较低。CAR重定向的常规CD4⁺细胞和Treg细胞的不同溶细胞能力意味着它们在细胞治疗中有不同用途。
