1-s2.0-S1074761319305266-main.pdf (6.77 MB)

Regulatory T cells restrain interleukin-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cells.

Download (6.77 MB)
journal contribution
posted on 22.10.2020, 13:27 by Anna 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.