Understanding the development of resident memory T cells in the human small intestine using integrative multiomic approaches (PI Raquel Bartolome Casado)

Tissue-resident memory T cells (TRM) are permanently lodged in barrier tissues like the gut, and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM are poorly understood. By exploiting a unique human intestinal transplantation setting where we can directly distinguish persisting TRM from circulating T cells, we have recently shown that the human small intestine contains large populations of long-lived CD4+ and CD8+ T cells. We will now use this transplantation model to identify mechanisms and anatomical niches that promote and support the development and maintenance of TRM cells. 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 and a world-leading expert in the field of single-cell genomics and its application to T-cell biology. Postdoc Raquel Bartolome-Casado will spend two years (from June-2021) in Dr. Teichmann’s lab to apply cutting-edge multiomic single-cell technologies, including parallel epigenetic, transcriptomic and T cell receptor analysis, to decipher the developmental pathways of human gut TRM cells. 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.

Drawing of transplanted pancreas with a piece of duodenum (left). Percentage of donor CD8+ T  cells  in donor duodenum at different time points after transplantation (right). CD103- lamina propria cells (LPCs, red), CD103+ LPCs (blue), and CD103+ intraepithelial cells (IELs) (green). Adapted from Casado et al. JEM, 2019.