Regulatory T cells restrain interleukin-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cellsMore about Open Access at the Crick
Authors listAnna Śledzińska Maria Vila de Mucha Katharina Bergerhoff Alastair Hotblack Dafne Franz Demane Ehsan Ghorani Ayse U Akarca Maria AV 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 Jenner Karl S Peggs Sergio A Quezada
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.
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