Journal
IMMUNITY
Volume 52, Issue 1, Pages 151-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2019.12.007
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Funding
- Cancer Research UK (CRUK) senior cancer research fellowship [C36463/A22246]
- CRUK career development fellowship [536392/170773]
- CRUK biotherapeutic program grant [C36463/A20764]
- NIHR BTRU for Stem Cells and Immunotherapies [167097]
- Cancer Research Institute investigator award
- Worldwide Cancer Research grant
- UCL/UCL Hospitals Biomedical Research Centre
- CRUK-UCL Centre [C416/A18088]
- Cancer Immunotherapy Accelerator Award (CITA-CRUK) [C33499/A20265]
- Bloodwise [08022/P4664]
- Department of Health
- CRUK
- MRC [MR/R001413/1]
- ERC [CoG 647215]
- MRC [MR/M003493/1, MR/R001413/1] Funding Source: UKRI
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In addition to helper and regulatory potential, CD4(+) T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4(+) T cells following immunotherapy. CD4(+) transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4(+), and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-gamma (IFN-gamma) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4(+) T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4(+) T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.
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