Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes

Abstract

Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to compare the proteomes of induced T-IEL and natural T-IEL subsets, with naive CD8+ T cells from lymph nodes. This data exposes the dominant effect of the gut environment over ontogeny on T-IEL phenotypes. Analyses of protein copy numbers of >7000 proteins in T-IEL reveal skewing of the cell surface repertoire towards epithelial interactions and checkpoint receptors; strong suppression of the metabolic machinery indicating a high energy barrier to functional activation; upregulated cholesterol and lipid metabolic pathways, leading to high cholesterol levels in T-IEL; suppression of T cell antigen receptor signalling and expression of the transcription factor TOX, reminiscent of chronically activated T cells. These novel findings illustrate how T-IEL integrate multiple tissue-specific signals to maintain their homeostasis and potentially function.

Distinct cell death pathways induced by granzymes collectively protect against intestinalSalmonellainfection

“…That IEL express granzymes constitutively at steady-state has been known for a long time, however the function of IEL-expressed Gzms is unknown. More than 80% of IEL express GzmA and GzmB, and previous proteomic analyses showed that IEL subsets express up to 20 million molecules of GzmA and ~5 million molecules of GzmB per cell (Brenes et al, 2021).…”

“…One subset of T lymphocytes that constitutively express GzmA and GzmB are intestinal intraepithelial T lymphocytes (IEL) (Brenes et al, 2021;Shires et al, 2001). IEL are a heterogenous population of T cells that occupy the intracellular space between intestinal epithelial cells.…”

“…Induced IEL consist of conventional TCRαβ CD8αβ T cells while natural IEL, characterized by the expression of CD8αα, are defined as TCRαβ CD8αα or TCRγδ CD8αα T cells. Despite developmental differences, both types of IEL are characterized by an activated phenotype characterized by very high expression of GzmA and B, and lower expression of GzmC and GzmK (Brenes et al, 2021). Based on the tissue location and cytotoxic potential of IEL, the cells have been postulated to play a key role in defending against intestinal infection.…”

Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells

“…KIR3DL3+ T cells in peripheral blood share many attributes with unconventional IELs, which have been described as having a "resting-but-activated" phenotype 95 . Innate-like CD8αα+ intraepithelial T cells are enriched for auto-reactive T cells, can be hyporesponsive to TCR engagement, are Vδ1-biased, rearrange TCR-α chains early in agonistic thymic selection, and upregulate NK cell inhibitory receptors and TCR-responsive genes 90,[95][96][97] . The transcriptional profile, cell surface receptor phenotype (CD3 low CD27 hi CD69+CD56+), and TCR repertoire of KIR3DL3-expressing T cells reflect these features.…”

The Immunological Proteome Resource

“…4b). The dataset characterises the proteome of TCRαβ CD8αβ, TCRαβ CD8αα and TCRγd CD8αα T-IELS along with two conventional TCRαβ CD8αβ lymph node derived naïve CD8+ T cell populations, wild type (WT) and P14 21 . The raw files and MaxQuant output for this dataset are available in PRIDE with identifier PXD023140 22 , while the processed copy numbers are available in the ‘Downloads’ tab in ImmPRes.…”