期刊
CELL
卷 184, 期 15, 页码 3998-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.05.027
关键词
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资金
- Melanoma Research Foundation
- NIH [R01 AI123349, R21 AR072849]
- Elizabeth O'Brien/Charles King Trust fellowship
- Shakhmardan Yessenov Foundation
- Nazarbayev University
- Italian Biochemistry Society (SIB)
- DFG [PR 1652/1-1]
The study reveals that T regulatory cells interact with tumor-associated conventional dendritic cells to receive activation signals and self-regulate their function through a CTLA-4- and CD28-dependent feedback loop. CTLA-4 blockade may lead to Treg cell hyper-proliferation and impact therapeutic benefits in cancer patients.
Foxp3(+) T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.
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