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

Immunity. 2020 Jan 14;52(1):151-166.e6. doi: 10.1016/j.immuni.2019.12.007. Epub 2020 Jan 7.

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.

Keywords: Blimp-1; CD4-mediated anti-tumor response; IL-2; T-bet; Treg depletion; anti-CTLA-4; cytotoxic CD4(+) T cells; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Line, Tumor
  • Granzymes / immunology*
  • Humans
  • Interferon-gamma / immunology
  • Interleukin-2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / immunology*
  • Positive Regulatory Domain I-Binding Factor 1 / metabolism*
  • T-Box Domain Proteins / metabolism*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation*
  • Tumor Microenvironment / immunology

Substances

  • IFNG protein, mouse
  • Interleukin-2
  • Prdm1 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interferon-gamma
  • Positive Regulatory Domain I-Binding Factor 1
  • Granzymes
  • Gzmb protein, mouse