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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Understanding the development of resident memory T cells (Trm) in the human small intestine using integrative multiomic approaches

Alternative title: Studie av vevsresidente hukommelses T-celler (Trm) i human tynntarmen med integrerende multiomiske teknikker.

Awarded: NOK 3.9 mill.

T cells are immune cells that can directly recognize and eliminate foreign agents (antigens), protecting us against infections and cancer. The goal of vaccination is to establish long-lasting immunological memory, in which memory T cells constitute a crucial component. The peripheral tissues in our body (such as skin, lungs and gut) harbor numerous resident memory T cells (Trm), strategically located at the front-line to quickly and efficiently fight pathogens. As such, Trm cells represent promising targets for novel vaccines, but have been also involved in dysregulated responses leading to autoimmune and inflammatory disorders. During the last decade, diverse mouse studies have shed light on Trm differentiation and effector responses to diverse pathogens. However, translating these results into humans is still a challenging task. In our lab, by examining T cells in intestinal grafts over a one-year period, we have recently demonstrated that the human small intestine contains substantial populations of long-lived Trm cells. We will now use this unique transplantation material to identify the mechanisms that promote the development and maintenance of intestinal Trm cells in humans. To this end, we will partner with Sarah Teichmann at the Wellcome Sanger Institute in Cambridge, UK, who is a co-founder of the Human Cell Atlas Consortium. We will apply cutting-edge technologies to dissect the heterogeneity of Trm cells at single-cell resolution, including parallel epigenetics, transcriptomics, proteomics and T cell receptor analysis. This integrative approach will allow us to decipher the developmental pathways of human gut Trm cells. The results expected from this project will provide unprecedented knowledge on the mechanisms of immune memory development in the human gut, which has major implications for long-lasting oral vaccination strategies and treatments of intestinal immune disorders involving persistent pathogenic T cells.

Animal studies have demonstrated that resident memory T (Trm) cells provide enhanced protective responses to a broad array of tissue-tropic pathogens, thus making Trm cells promising targets for novel vaccination strategies. However, the biological pathways that enable the long-term survival of Trm cells are poorly understood in humans. Here, we will employ a unique human intestinal transplantation setting that allows us to study the retention of persistent T cells in the grafts and the temporal development of resident T-cell populations from recruited recipient T cells. We will integrate high resolution transcriptomics, epigenetics, proteomics and immune repertoire single-cell data from purified intestinal T cells. These single-cell multiomics approaches will uncover the diversity and differentiation of the T cell populations in the human intestine, allowing us to temporally resolve the generation and maintenance of gut resident T cells.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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