The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.
The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.
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DOI：
10.3389/fimmu.2021.639818
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tang Q
中科院分区：
文献类型：
--
作者：
Muller YD;Nguyen DP;Ferreira LMR;Ho P;Raffin C;Valencia RVB;Congrave-Wilson Z;Roth TL;Eyquem J;Van Gool F;Marson A;Perez L;Wells JA;Bluestone JA;Tang Q
抗cd19嵌合抗原受体（CD19-CAR）工程T细胞已被批准用于恶性肿瘤的治疗。细胞外抗原靶向CARs与细胞内信号转导方式之间的铰链结构域（HD）和跨膜结构域（TMD）的影响尚未得到系统的研究。在这项研究中，产生了一系列19- car，它们只是HD （CD8、CD28或IgG4）和TMD （CD8或CD28）不同。含有CD28- tmd而非CD8-TMD的car在人T细胞中与内源性CD28形成异源二聚体，这可以通过免疫共沉淀和抗CD28刺激的car依赖性增殖来证明。这种二聚化依赖于CD28- tmd中的极性氨基酸，并且在含有CD28或CD8 HD的car中比含有IgG4-HD的car更有效。CD28- car异二聚体对CD80和CD86刺激没有反应，但CD28细胞表面表达显著降低。这些数据揭示了CD28-TMD和CD8-TMD之间的根本差异，并表明CD28-TMD可以通过参与内源性伴侣来调节CAR - t细胞的活性。
Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG4) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG4-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.
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影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
10.1
作者：
Frigault MJ;Lee J;Basil MC;Carpenito C;Motohashi S;Scholler J;Kawalekar OU;Guedan S;McGettigan SE;Posey AD Jr;Ang S;Cooper LJ;Platt JM;Johnson FB;Paulos CM;Zhao Y;Kalos M;Milone MC;June CH
通讯作者：
June CH
影响因子：
45.3
作者：
Kochenderfer, James N.;Somerville, Robert P. T.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
7.5
作者：
Maziarz, Richard T.;Schuster, Stephen J.;Locke, Frederick L.
通讯作者：
Locke, Frederick L.