Abstract
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.
Original language | English (US) |
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Pages (from-to) | 3998-4015.e19 |
Journal | Cell |
Volume | 184 |
Issue number | 15 |
DOIs | |
State | Published - Jul 22 2021 |
Externally published | Yes |
Keywords
- CD28
- CTLA-4
- MP-IVM
- NFAT
- T regulatory cell
- Treg cell
- cytotoxic T lymphocyte-associated protein 4
- multiphoton intravital microscopy
- nuclear factor of activated T cells
- tumor tolerance
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology