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Generation of Induced Regulatory T Cells from Primary Human Naïve and Memory T Cells
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Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

Anna Śledzińska1, Maria Vila de Mucha2, Katharina Bergerhoff1

  • 1Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK.

Immunity
|January 12, 2020
PubMed

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-1CD4-mediated anti-tumor responseIL-2T-betTreg depletionanti-CTLA-4cytotoxic CD4(+) T cellsregulatory T cells

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