CD4 Inhibits Helper T Cell Activation at Lower Affinity Threshold for Full-Length T Cell Receptors Than Single Chain Signaling Constructs

被引:3
|
作者
Johnson, Deborah K. [1 ]
Magoffin, Wyatt [1 ]
Myers, Sheldon J. [1 ]
Finnell, Jordan G. [2 ]
Hancock, John C. [1 ]
Orton, Taylor S. [1 ]
Persaud, Stephen P. [3 ]
Christensen, Kenneth A. [2 ]
Weber, K. Scott [1 ]
机构
[1] Brigham Young Univ, Dept Microbiol & Mol Biol, Provo, UT 84602 USA
[2] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA
[3] Washington Univ, Div Lab & Genom Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
来源
FRONTIERS IN IMMUNOLOGY | 2021年 / 11卷
基金
美国国家卫生研究院;
关键词
CD4; T cell receptor; affinity; chimeric antigen receptor; Lck; helper T cell; TELOMERASE PEPTIDE VACCINATION; RECOGNITION SPECIFICITY; CRYSTAL-STRUCTURE; TERNARY COMPLEX; PHASE-I/II; ALPHA-BETA; TCR-ALPHA; IN-VITRO; ANTIGEN; MHC;
D O I
10.3389/fimmu.2020.561889
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
CD4(+) T cells are crucial for effective repression and elimination of cancer cells. Despite a paucity of CD4(+) T cell receptor (TCR) clinical studies, CD4(+) T cells are primed to become important therapeutics as they help circumvent tumor antigen escape and guide multifactorial immune responses. However, because CD8(+) T cells directly kill tumor cells, most research has focused on the attributes of CD8(+) TCRs. Less is known about how TCR affinity and CD4 expression affect CD4(+) T cell activation in full length TCR (flTCR) and TCR single chain signaling (TCR-SCS) formats. Here, we generated an affinity panel of TCRs from CD4(+) T cells and expressed them in flTCR and three TCR-SCS formats modeled after chimeric antigen receptors (CARs) to understand the contributions of TCR-pMHCII affinity, TCR format, and coreceptor CD4 interactions on CD4(+) T cell activation. Strikingly, the coreceptor CD4 inhibited intermediate and high affinity TCR-construct activation by Lck-dependent and -independent mechanisms. These inhibition mechanisms had unique affinity thresholds dependent on the TCR format. Intracellular construct formats affected the tetramer staining for each TCR as well as IL-2 production. IL-2 production was promoted by increased TCR-pMHCII affinity and the flTCR format. Thus, CD4(+) T cell therapy development should consider TCR affinity, CD4 expression, and construct format.
引用
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页数:18
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