Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.561889
Keywords
CD4; T cell receptor; affinity; chimeric antigen receptor; Lck; helper T cell
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Funding
- R15 grant from the National Institutes of Health [R0102063]
- Simmons Center for Cancer Research Summer Fellowships
- Brigham Young University
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CD4(+) T cells are important for suppressing and eliminating cancer cells, and their activation is influenced by CD4 expression and TCR affinity. The coreceptor CD4 inhibits TCR activation through various mechanisms. TCR-pMHCII affinity and construct format impact IL-2 production and tetramer staining for each TCR.
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.
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