TY - JOUR TI - Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes AU - Brenes, Alejandro J AU - Vandereyken, Maud AU - James, Olivia J AU - Watt, Harriet AU - Hukelmann, Jens AU - Spinelli, Laura AU - Dikovskaya, Dina AU - Lamond, Angus I AU - Swamy, Mahima A2 - Rothlin, Carla V VL - 10 PY - 2021 DA - 2021/09/02 SP - e70055 C1 - eLife 2021;10:e70055 DO - 10.7554/eLife.70055 UR - https://doi.org/10.7554/eLife.70055 AB - 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 T-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. KW - T lymphocytes KW - intestinal immunity KW - proteomics KW - immunometabolism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -