Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

Anna Śledzińska, Maria Vila de Mucha, Katharina Bergerhoff, Alastair Hotblack, Dafne Franz Demane, Ehsan Ghorani, Ayse U. Akarca, Maria A.V. Marzolini, Isabelle Solomon, Frederick Arce Vargas, Martin Pule, Masahiro Ono, Benedict Seddon, George Kassiotis, Charlotte E. Ariyan, Thomas Korn, Teresa Marafioti, Graham M. Lord, Hans Stauss, Richard G. JennerKarl S. Peggs*, Sergio A. Quezada

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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-γ (IFN-γ) 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. Śledzińska et al. show that upon depletion of regulatory T cells, a surplus of interleukin-2 in the tumor microenvironment supports acquisition of cytotoxic activity by T helper cells orchestrated by the transcription factor Blimp-1. These polyfunctional CD4+ T cells exhibit potent anti-tumor activity in an adoptive transfer setting with therapeutic implications.

Original languageEnglish
Pages (from-to)151-166.e6
JournalImmunity
Volume52
Issue number1
DOIs
StatePublished - 14 Jan 2020
Externally publishedYes

Keywords

  • Blimp-1
  • CD4-mediated anti-tumor response
  • IL-2
  • T-bet
  • Treg depletion
  • anti-CTLA-4
  • cytotoxic CD4 T cells
  • regulatory T cells

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