Nicolet, B. | Search bioRxiv

bioRxiv2022

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

2-hydroxyglutarate (2HG) is a by-product of the TCA cycle, and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in CD8+ T cell biology, where we found they had highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific a-ketoglutarate (aKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo, and enhanced anti-tumour activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

immunology↗

bioRxiv2021

Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function

Potent T cell responses against infections and malignancies depend on the release of effector molecules, such as pro-inflammatory cytokines. Because effector molecules can be toxic, their production is tightly regulated through post-transcriptional events at 3 Untranslated Regions (3UTRs). RNA binding proteins (RBPs) were shown to be key regulators herein. With an RNA aptamer-based capture assay from human T cells, we identified >130 RBPs interacting with the IFNG, TNF and IL2 3UTRs in human T cells. T cell activation altered RBP-RNA interactions, revealing that RBP-target mRNA interactions rapidly respond to stimulation. Furthermore, we uncovered the intricate and time-dependent regulation of cytokine production by RBPs: whereas HuR supports early cytokine production, ZFP36L1, ATXN2L and ZC3HAV1 dampen and shorten the production duration, each at different time points. Strikingly, even though ZFP36L1 deletion did not phenotypically rescue T cell dysfunction in tumors, the increased production of cytokines and cytotoxic molecules resulted in superior anti-tumoral T cell responses in vivo. Our findings thus show that identifying RBP-RNA interactions reveals key modulators of T cell responses in health and disease.

immunology↗