Newly Generated CD4+ T Cells Acquire Metabolic Quiescence after Thymic Egress

Abstract

Mature naive T cells circulate through the secondary lymphoid organs in an actively enforced quiescent state. Impaired cell survival and cell functions could be found when T cells have defects in quiescence. One of the key features of T cell quiescence is low basal metabolic activity. It remains unclear at which developmental stage T cells acquire this metabolic quiescence. We compared mitochondria among CD4 single-positive (SP) T cells in the thymus, CD4 recent thymic emigrants (RTEs), and mature naive T cells in the periphery. The results demonstrate that RTEs and naive T cells had reduced mitochondrial content and mitochondrial reactive oxygen species when compared with SP thymocytes. This downregulation of mitochondria requires T cell egress from the thymus and occurs early after young T cells enter the circulation. Autophagic clearance of mitochondria, but not mitochondria biogenesis or fission/fusion, contributes to mitochondrial downregulation in RTEs. The enhanced apoptosis signal-regulating kinase 1/MAPKs and reduced mechanistic target of rapamycin activities in RTEs relative to SP thymocytes may be involved in this mitochondrial reduction. These results indicate that the gain of metabolic quiescence is one of the important maturation processes during SP-RTE transition. Together with functional maturation, it promotes the survival and full responsiveness to activating stimuli in young T cells.

Cutting Edge: Glycolytic Metabolism and Mitochondrial Metabolism Are Uncoupled in Antigen-Activated CD8+ Recent Thymic Emigrants

“…To determine mitochondrial mass, RTEs and mature T cells were left resting or activated ± exogenous IL-2 and the level of VDAC1 determined. Resting CD8 + RTEs and mature T cells had equivalent VDAC1 levels, similar to recent observations in resting CD4 + RTEs (36). However, upon activation, RTEs expressed significantly less VDAC1 than their mature T cell counterparts (Fig.…”

Mevalonate metabolism–dependent protein geranylgeranylation regulates thymocyte egress

“…For instance, we recently described dynamic rewiring of metabolic programs in early thymocyte development and a key role for anabolic and oxidative metabolism in directing αβ and γδ T cell fate decisions (Yang et al, 2018). Interestingly, thymic egress is required for the establishment of metabolic quiescence in recent thymic emigrants (Zhang et al, 2018), and S1P 1 orchestrates energetic fitness of naive T cells in the periphery (Mendoza et al, 2017). However, whether and how thymocyte egress is regulated by cellular metabolism and the underlying signaling pathways remain unclear.…”

DNA Methylation Patterns in CD4+ T Cells of Naïve and Influenza A Virus-Infected Mice Developmentally Exposed to an Aryl Hydrocarbon Receptor Ligand

“…A simplistic explanation is that this reflects the overall lack of overt changes to immune system development in mice developmentally exposed to this dose of AhR agonist (Boule et al 2014;Vorderstrasse et al 2004). Yet, a more likely explanation is the transcriptionally quiescent state of resting CD4 + T cells in the absence of an immune challenge (Feng et al 2010(Feng et al , 2011Zhang et al 2018). The dearth of DEGs in naïve CD4 + T cells is similar to observations in CD8 + T cells from uninfected offspring of TCDD and control treated dams, in which there were only a handful of DEGs (Winans et al 2015).…”