Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer
Name
nihms-1958878.pdf
Description
Accepted version
Size
3.28 MB
Format
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Checksum (MD5)
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Author(s)
Zagorulya, Maria
Yim, Leon
Morgan, Duncan M
Edwards, Austin
Torres-Mejia, Elen
Momin, Noor
McCreery, Chloe V
Zamora, Izabella L
Horton, Brendan L
Fox, James G
Date Issued
February 14, 2023
Journal
Immunity
Publisher
Elsevier BV
Citation
Zagorulya, Maria, Yim, Leon, Morgan, Duncan M, Edwards, Austin, Torres-Mejia, Elen et al. 2023. "Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer." Immunity, 56 (2).
Version
Author's final manuscript
Abstract
Local environmental factors influence CD8+ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8+ T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8+/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Division of Comparative Medicine
Ragon Institute of MGH, MIT and Harvard
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Creative Commons Attribution-Noncommercial-ShareAlike
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DOI of Published Version
https://doi.org/10.1016/j.immuni.2023.01.010
