Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion

Nat Immunol. 2019 Jun;20(6):724-735. doi: 10.1038/s41590-019-0346-9. Epub 2019 Apr 1.


Regulatory T cells (Treg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3-IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8+ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8+ TILs that limits effective anti-tumor immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression Profiling
  • Humans
  • Immunity, Cellular*
  • Interleukin-10 / metabolism*
  • Interleukins / metabolism*
  • Melanoma, Experimental
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Transcriptome


  • Cytokines
  • IL10 protein, human
  • Interleukins
  • interleukin-35, human
  • Interleukin-10