Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes

Abstract

Epithelial-resident T lymphocytes, such as intraepithelial lymphocytes (IELs) located at the intestinal barrier, can offer swift protection against invading pathogens. Lymphocyte activation is strictly regulated because of its potential harmful nature and metabolic cost, and most lymphocytes are maintained in a quiescent state. However, IELs are kept in a heightened state of activation resembling effector T cells but without cytokine production or clonal proliferation. We show that this controlled activation state correlates with alterations in the IEL mitochondrial membrane, especially the cardiolipin composition. Upon inflammation, the cardiolipin composition is altered to support IEL proliferation and effector function. Furthermore, we show that cardiolipin makeup can particularly restrict swift IEL proliferation and effector functions, reducing microbial containment capability. These findings uncover an alternative mechanism to control cellular activity, special to epithelial-resident T cells, and a novel role for mitochondria, maintaining cells in a metabolically poised state while enabling rapid progression to full functionality.

Metabolic wiring of murine T cell and intraepithelial lymphocyte maintenance and activation

“…The appearance of mitochondria is in line with the high respiratory capacity at day one of T‐cell activation, followed by reduced capacity in subsequent days (Fig. B and C) .…”

“…Using this methodology, naive T cells show limited additional oxygen consumption rate (OCR, mitochondrial respiration) compared with basal level respiration, termed the spare respiratory capacity (SRC). On the other hand, recently activated T cells (24 h) have a markedly higher glycolysis rate and SRC (increased mitochondrial respiration) . At later time points (days 6–7) effector T cells do no longer show an enhanced SRC , in line with repression of gene transcripts involved in glycolysis and their recurrence to basal state .…”

“…The apparent opposing pathways could be maintained simultaneously in memory T cells to ensure pathway readiness, however, this would come at significant metabolic costs. Products of FAS, fatty acids and cholesterol esters, can be stored in the form of lipid droplets, during the effector T‐cell phase . These droplets may be consumed in the differentiation process from effector to memory cell and in FAO in the memory cell state.…”

“…In line with the concept of metabolic rewiring, memory T cells show an increased oxidative consumption rate upon mitochondrial uncoupling compared with naive T cells. This suggests a higher metabolic potential that is similar to recently activated T cells that can be explained by increased expression of electron transport chain (ETC) proteins in memory T cells , which enhance the metabolic potential without necessarily requiring more energy during their quiescent state. Memory T cells have more mitochondria with larger membrane surface area compared to naive T cells, which together with increased expression of ETC proteins, underpin the enhanced OXPHOS potential.…”

“…These tissues are occupied by an innate‐like population of T cells prior to birth, which are intercalated with T RM cells developing throughout life . These cell populations, collectively referred to as intraepithelial lymphocytes (IELs), are kept in a heightened state of cell activation . IELs are not undergoing proliferative burst nor actively secrete effector molecules and appear hence, like naive and memory T cells, to be in a state of quiescence.…”