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

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 cell (Treg)depletion promoted GzmB expression by tumor-infiltrating CD4+which was prevented by IL-2 neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized bythe expression of the transcription factors T-bet and Blimp-1. Whilst T-bet ablation restrictedIFN-gproduction, lossof Blimp-1preventedGzmB expressionin response to IL-2, suggesting these are two independent programs required forpolyfunctionality of tumor-reactive CD4+T cells. The data underscores the role of Treg, IL-2 and Blimp-1 controlling the differentiation of cytotoxic T cells and offers a pathway to enhancement of anti-tumor activity through their manipulation.

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Śledzińska A, Vila de Mucha M, Bergerhoff K, Hotblack A, Demane DF, Ghorani E, Akarca AU, Marzolini MAV, Solomon I, Vargas FA, Pule M, Ono M, Seddon B, Kassiotis G, Ariyan CE, Korn T, Marafioti T, Lord GM, Stauss H, Jenner RG, Peggs KS, Quezada SA