Together with the Jagannathan lab at Stanford University, we (Midhuna and Adam) explored how repeated malaria infections reshape the transcriptional regulation through the epigenome and function of Vδ2+ T cells.
Vδ2+ T cells help fight malaria through inflammatory and cytotoxic responses, but in children who have had malaria many times these cells respond less strongly. We profiled Vδ2+ T cells from Ugandan children, comparing cohorts with high and low transmission and following children over time as transmission dropped, using paired bulk ATAC-seq and RNA-seq as well as CITE-seq. Higher malaria exposure was linked to lower TNF and IFNγ production and to thousands of differentially accessible chromatin regions, with immunoregulatory genes such as LYN, PLCG2 and HAVCR2 (Tim-3) gaining accessibility and pro-inflammatory genes and AP-1 motifs losing it. In an in vitro model, repeated stimulation reproduced this hyporesponsive state, which the tyrosine kinase inhibitor dasatinib partially reversed, pointing to possible ways to restore the function of these cells.
We thank first author Kathleen D. Press and all co-authors, especially Prasanna Jagannathan (Stanford University), who led the study. We are also grateful to our collaboration partners in the labs of William Greenleaf and Sandy Klemm. Above all, we thank the children and families who took part in the cohort studies.
Read the full preprint on bioRxiv: https://doi.org/10.64898/2026.10.02.755737