Unravelling immunoregulatory circuits of T cells

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In this fiscal year we made the following research observations that have been peer reviewed and published: 1. We used deep phenotyping methods to look for populations of anti-inflammatory immune cells (regulatory T cells) with unique properties. We found one such population that that highly anti-inflammatory properties but that also produced soluble factors normally restricted to inflammatory immune cells. By leveraging state of the art genome interrogation methods we identified how the unique properties of these cells were regulated and that the soluble factors they produced accelerated wound healing. We found them to be enriched in the gut and that they appeared to be beneficial in inflammatory bowel disease. These properties suggest that these cells may be beneficial in programs of cell-based therapy for the treatment of inflammatory bowel disease in humans. This work was published in Nature Immunology. 2. We have a strong interest in how how factors produced in tissues affect T cell biology, since these are particularly relevant to what T cells do when they reach sites of inflammation, such as the kidneys. One of the key kidney-relevant systems is the complement system. Together with one of our main collaborators in NHLBI we established this year that complement receptor engagement on CD8 cells is a requirement for optimal function of these cells for fighting viral infections. Such signals altered fatty acid metabolism in CD8 cells, which is of note because it is being increasingly recognized that altering metabolic function of cells is a key means by which immune cells are regulated. This work was published in Nature Communications. We followed this up with a review article in Advances in Immunology detailing some of the means by which the complement system regulates T cell behavior. 3. An essential transcription factor in anti-inflammatory T cells is called STAT5. Together with colleagues in NIAID we were involved in the description of an unexpected role of STAT5 signaling in the death of inflammatory types of T cells in both mice and humans. As part of this, we described a unique patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. The protein mutation had a dominant negative effect over the normal copy of the gene, thus causing disease despite the patient having only one abnormal gene copy. This paper was published in the Journal of Immunology. 4. Because we use cutting edge genome interrogation methods, it is important for our group to be at the forefront of computational methods for data analysis and integration. For this purpose we have a long-term collaboration with Prof Kazemian at Purdue university, who runs a dry (computational) and wet lab. We have been working on methodology for interrogation of dark matter in sequencing data. Such data is mostly sequenced information from viruses that have infected cells, but that are normally ignored because they do not "map" to the human genome. By focussing specifically on this information and leveraging such data from >1000 RNA sequencing data sets, we made some novel observations about Epstein-Barr virus infections in humans, which is a major cause of lymphoid malignancies. A comprehensive host-pathogen interactome map was created and some interesting observations regarding what the virus does to host cells and vice versa were made. This work could help in the selection of individualized therapies for patients with EBV-associated cancers and was published in Cancer Research.