Intrinsic Impairment of CD8 T Cells Induced by Helminth Coinfection

Abstract

Abstract Although it is known that helminth-triggered type 2 response increases host vulnerability to coinfections and potentially decreases vaccine efficacy, the exact mechanism(s) for the helminth-induced immunomodulation is still a fundamental question in the field. We have previously reported that CD44hiCD62L−KLRG1+ effector CD8 T cells from mice coinfected with Heligmosomoides polygyrus (H. polygyrus) and Toxoplasma gondii (T. gondii) exhibit a suppressed effector differentiation and impaired IFNγ production upon in vitro re-stimulation with toxoplasma antigens. This impairment was accompanied by a decrease in both, mitochondrial biomass and gene expression of the mitochondrial transcription factor, TFB1M. Further analysis of CD44hiT. gondii-specific CD8 T cells via single cell RNAseq, revealed an effector CD8 T cell subset from coinfected mouse that exhibit down-regulation of Cox17 and Atp5k transcripts. Both of these transcripts encode for proteins that belong to the electron transport chain multimeric complexes III and V, respectively. Taken altogether, our data suggest a potential metabolic-dependent mechanism of effector CD8 T cell insufficiency induced by helminth-coinfection. We hypothesize that helminth infection results in an impairment of CD8 T cell metabolic reprogramming, thus, affecting their effector development and function in response to T. gondii infection. The aim of this work is to increase the understanding of the helminth-associated immunomodulatory mechanism of CD8 T cells with the objective of finding therapeutic ways to restore CD8 T cells effector functions to improve vaccine efficacy in helminth-affected subpopulations.