Repeated malaria exposure reprograms Vδ2+ γδT cell chromatin accessibility and immune function toward a reversible hyporesponsive state
- 1Stanford University
Abstract
V{delta}2+ {gamma}{delta} T cells contribute to antimalarial immunity via pro-inflammatory and cytotoxic mechanisms. Among children who have experienced repeated episodes of malaria, V{delta}2+ T cells develop reduced pro-inflammatory function through mechanisms that remain unknown. We hypothesized that recurrent malaria drives coordinated epigenetic and transcriptional remodeling of these semi-innate cells. Using PBMC from Ugandan children in cohorts spanning high and low transmission (10 children) and longitudinally across a marked decline in transmission (20 children, 3 timepoints), we profiled the epigenome and transcriptome of V{delta}2+ T cells by paired bulk ATAC-seq and RNA-seq and by CITE-seq. Higher malaria exposure was associated with reduced V{delta}2+ T cell TNF and IFN{gamma} production and with thousands of differentially accessible chromatin regions. Immunoregulatory genes including LYN, PLCG2, and HAVCR2 (Tim-3) showed increased chromatin accessibility and/or expression at high exposure, whereas pro-inflammatory gene (IFNG, GZMK, IL7R) and AP-1 (JUN/FOS) motif accessibility were increased at low exposure; linkage of regulatory elements with target genes corroborated these associations. Single-cell transcriptional analysis identified a cytotoxic CD8+CD16+CD57+ V{delta}2+ T cell subset. In our in vitro model, repeated stimulation with malaria-infected red blood cells or the phosphoantigen HMBPP was similarly associated with reduced V{delta}2+ T cell degranulation and cytokine production. Diminished responsiveness was predominantly TCR-dependent, accompanied by heightened p38 signaling, and was partially reversed by rest induced by the tyrosine kinase inhibitor dasatinib. Together these data reveal how repeated malaria may reshape cellular immunity by reprogramming V{delta}2+ T cells toward a reversible, hyporesponsive state and highlight targets for therapeutically restoring their function.
Related
- Genome-wide loss of chromatin accessibility coexists with selectively elevated RNA abundance in nutrient-starved U2OS cells
- An expanded evolutionary landscape of H3 histones with variants that destabilize nucleosomes and promote chromatin accessibility
- Reversible chromatin remodeling enables Prosopis cineraria survival under recurrent heat extremes.
- ATACofthesnake: A scalable framework for analyzing multifactorial and time course chromatin accessibility data
- Sulforaphane, A Mustard Oil Bomb Product, Reprograms Herbivore Gene Expression and Alters Chromatin Structure Across Generations
BibTeX
@misc{press2026repeated,
title = {{Repeated malaria exposure reprograms Vδ2+ γδT cell chromatin accessibility and immune function toward a reversible hyporesponsive state}},
author = {K. D. Press and M. I. J. Maran and A. Ashkar-Masarwa and K. Camanag and D. Chen and V. Shokoohi and A. Kathiria and M. Ty and J. Nideffer and J. Rek and J. Nankabirwa and F. Nankya and J. Schulze-Hentrich and I. Ssewanyana and M. Kamya and M. Boyle and B. Greenhouse and G. Dorsey and M. Feeney and W. Greenleaf and S. Klemm and F. Muller and P. Jagannathan},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.755737},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.755737v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Repeated malaria exposure reprograms Vδ2+ γδT cell chromatin accessibility and immune function toward a reversible hyporesponsive state
AU - K. D. Press
AU - M. I. J. Maran
AU - A. Ashkar-Masarwa
AU - K. Camanag
AU - D. Chen
AU - V. Shokoohi
AU - A. Kathiria
AU - M. Ty
AU - J. Nideffer
AU - J. Rek
AU - J. Nankabirwa
AU - F. Nankya
AU - J. Schulze-Hentrich
AU - I. Ssewanyana
AU - M. Kamya
AU - M. Boyle
AU - B. Greenhouse
AU - G. Dorsey
AU - M. Feeney
AU - W. Greenleaf
AU - S. Klemm
AU - F. Muller
AU - P. Jagannathan
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.755737
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.755737v1
AB - V{delta}2+ {gamma}{delta} T cells contribute to antimalarial immunity via pro-inflammatory and cytotoxic mechanisms. Among children who have experienced repeated episodes of malaria, V{delta}2+ T cells develop reduced pro-inflammatory function through mechanisms that remain unknown. We hypothesized that recurrent malaria drives coordinated epigenetic and transcriptional remodeling of these semi-innate cells. Using PBMC from Ugandan children in cohorts spanning high and low transmission (10 children) and longitudinally across a marked decline in transmission (20 children, 3 timepoints), we profiled the epigenome and transcriptome of V{delta}2+ T cells by paired bulk ATAC-seq and RNA-seq and by CITE-seq. Higher malaria exposure was associated with reduced V{delta}2+ T cell TNF and IFN{gamma} production and with thousands of differentially accessible chromatin regions. Immunoregulatory genes including LYN, PLCG2, and HAVCR2 (Tim-3) showed increased chromatin accessibility and/or expression at high exposure, whereas pro-inflammatory gene (IFNG, GZMK, IL7R) and AP-1 (JUN/FOS) motif accessibility were increased at low exposure; linkage of regulatory elements with target genes corroborated these associations. Single-cell transcriptional analysis identified a cytotoxic CD8+CD16+CD57+ V{delta}2+ T cell subset. In our in vitro model, repeated stimulation with malaria-infected red blood cells or the phosphoantigen HMBPP was similarly associated with reduced V{delta}2+ T cell degranulation and cytokine production. Diminished responsiveness was predominantly TCR-dependent, accompanied by heightened p38 signaling, and was partially reversed by rest induced by the tyrosine kinase inhibitor dasatinib. Together these data reveal how repeated malaria may reshape cellular immunity by reprogramming V{delta}2+ T cells toward a reversible, hyporesponsive state and highlight targets for therapeutically restoring their function.
ER -