Resolving CD4+ T helper fate bifurcation during malaria
Tapio Lönnberg1,2,#, Valentine Svensson1,#, Kylie R. James2,#, Oliver Stegle1,† Ashraful Haque3,†, Sarah A. Teichmann1,2,†
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, UK; 2Wellcome Trust Sanger Institute, Wellcome Genome Campus, UK; 3QIMR Berghofer Medical Research Institute, Queensland, Australia
# denotes equal contribution
† denotes equal contribution
CD4+ T helper cells are critical players in the immune response to many infectious diseases such as malaria. The cellular and molecular processes controlling the transition of naive CD4+ T cells into fully-activated, terminally differentiated T helper subsets, such as Th1 and Tfh cells in vivo remains to be determined. Here, we use single-cell RNAseq (scRNAseq) and computational modelling to explore at high resolution the differentiation of CD4+ T cells during infection. We show for the first time that after initial priming events, emerging Th cells entered a state of high cell cycling, in which they expressed genes associated with both Th1 and Tfh subsets. We demonstrate that galectin-1 promotes commitment to a Th1 fate. Furthermore, through additional scRNAseq analysis we identify a novel accessory role for monocytes, alongside conventional DCs, in supporting Th1 differentiation through the CXCR3/CXCL9 and CXCL10 chemokine axis. Timed depletion of monocytes supports an essential role in Th1 responses. In summary, we provide ex vivo evidence that during experimental blood-stage malaria clonal parasite-specific CD4+ T cells do not commit to their effector state until at least 3-4 days after initial priming. They require additional accessory signalling from cells such as monocytes before committing to their final differentiation state.
Funding was provided by Wellcome Trust, European Research Council, Australian National Health and Medical Research Council, University of Queensland, Australian Infectious Disease Research Centre and Lister Institute for Preventative Medicine. KRJ was supported by grants from EMBL Australia and OzEMalaR.