RT Journal Article
SR Electronic
T1 Alternative paths to immune activation: the role of costimulatory risk genes for polygenic inflammatory disease in T helper cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.23.517727
DO 10.1101/2022.11.23.517727
A1 Voda, Alexandru-Ioan
A1 Correa, Kristina
A1 Hamp, Jonathan
A1 Moscrop, Chloe
A1 Dustin, Michael
A1 Jostins-Dean, Luke
YR 2023
UL http://biorxiv.org/content/early/2023/02/01/2022.11.23.517727.abstract
AB T cell activation pathways have been repeatedly implicated by genetic studies as being enriched for risk genes for immune and inflammatory diseases. Many of these risk genes code for costimulatory receptors or ligands. Costimulatory receptors are cell surface proteins on T cells, which are engaged by costimulatory ligands on antigen-presenting cells. Both costimulation and antigen binding are required to trigger T cell activation. In order to study the different pathways activated by these costimulatory risk molecules, and the role they may play in inflammatory disease genetics, we carried out gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) profiling of naive and memory CD4+ T cells (N=5 donors) activated via four different costimulatory receptors: CD28 (the standard molecule used for in vitro activation studies), along with alternative costimulatory molecules ICOS, CD6, and CD27.Most, but not all, activation genes and regions are shared by different costimulation conditions. Alternative costimulation induced lower proliferation and cytokine production, but higher lysosome production, altered metabolic processing, and indications of “signal seeking” behaviour (homing and expression of costimulatory and cytokine receptors). We validated a number of these functions at the surface protein level using orthogonal experimental techniques. We found the strongest enrichment of heritability for inflammatory bowel disease in shared regions upregulated by all costimulatory molecules. However, some risk variants and genes were only induced by alternative costimulation, and the impact of these variants on expression were less often successfully mapped in studies of T cells activated by traditional CD28 costimulation. This suggests that future genetics studies of gene expression in activated T cells may benefit from including alternative costimulation conditions.Competing Interest StatementThe authors have declared no competing interest.