Unravelling immunoregulatory circuits of T cells

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Because of our interest in the factors that regulate tissue immunity and direct inflammatory versus regulatory functions of immune cells, we studied the genes induced in T cells as they enter a tissue site. We observed in RNA-seq of humans that immune cells that had migrated into lung tissues that one of the most highly induced pathways was the complement pathway and that complement factor 3 (C3) was one of the most highly induced genes. Using a reporter we confirmed these findings and went on to show that engagement of cell receptor receptors (LFA1) by cognate ligands on endothelial cells (ICAM-1) induced a transcriptional signal (AP-1) that led to transcription of C3. We went on to confirm the criticality of C3 expression in regulating cellular metabolism and "fitness" of immune cells to carry out inflammatory functions. Accordingly, T cells from patients with deficiency in LFA-1 manifesting as leukocyte adhesion disease 1 (LAD-1) had intrinsic defects in inflammatory function that could be restored proportionally by restoration of C3 expression inside the cells. This work was published in Immunity in 2020. Due to the SARS-Coronavirus (SARS-CoV2) pandemic, our primary efforts have been curtailed and we have had to switch focus to make contributions to our understanding of SARS-CoV2. We have two manuscripts currently under review, which will hopefully result in publications in FY21. The focus of both manuscripts is the regulation of local inflammation in lung tissues by factors primarily produced locally.