Dissecting the molecular mechanisms underpinning T cell help for Dendritic Cell

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Abstract CD8+ T cell priming relies on the ability of dendritic cells (DCs) to present antigen as well as to communicate contextual cues associated with antigen acquisition. Efficient CD8+ T cell response often requires DC interactions with helper CD4+ T cells through CD40-CD40L binding. Previously, our work showed that CD4+ T cell help amplifies the capacity of DCs to generate efficient priming of CD8+ T cell in response to suboptimal innate stimuli. Focusing on the CD40-driven amplification of innate pathways induced in IFN-α/β-stimulated DCs, this study explores the dynamics and molecular mechanisms underpinning such help phenotype. We have observed that the CD40-mediated amplification of IFN-α responses follows precise kinetics and affects only a portion of the innate stimulus-induced genes such as Il-15, Ccl5 or Tnf-α. Interestingly, a group of genes, unresponsive to IFN-α alone, required the combination of both stimuli to trigger their expression. These results highlighted the induction of two distinct patterns of gene regulation in response to CD40 and IFN-α stimulations, the amplified and the combinatorial. Based on transcriptomics, proteomics and phosphoproteomics data sets analyses, our data mining suggests the cooperation between IRFs and NF-κB transcription factors, acting in synergy towards the enhancement of DC responses and governing which genes can be amplified. Furthermore, the gene regulation and post-transcriptional modification of proteins involved in the regulation of NF-κB indicate a tight control of this signaling pathway. By dissecting how T cell help amplifies innate signals required for CD8+ T cell priming, this work will assist in the development of more targeted T-cell-based therapeutic strategies.