Credit: S. Bradbrook/NPG

T helper 17 (TH17) cells can be good or bad: on the one hand, they provide defence against extracellular pathogens and tissue homeostasis and, on the other hand, they can induce autoimmunity. In two linked studies published in Cell, researchers used single-cell RNA sequencing to investigate this functional heterogeneity and identify molecules that regulate the pathogenicity of TH17 cells. One candidate molecule, known as CD5L, regulates TH17 cell pathogenicity by modulating cellular fatty acid composition and thus ligand availability for the TH17 cell master transcription factor, RORγt.

Previous studies have shown that TH17 cells that are polarized in vitro with interleukin-1β (IL-1β), IL-6 and IL-23 adopt a more pathogenic state (that is, they can cause severe autoimmune responses upon adoptive transfer into mice), whereas TH17 cells polarized with transforming growth factor-β and IL-6 are non-pathogenic. The authors profiled the transcriptome of individual TH17 cells isolated from mice with experimental autoimmune encephalomyelitis (EAE) and compared them with the in vitro-differentiated TH17 cells. They found substantial heterogeneity in gene expression between individual cells raised in all conditions and, using a functional annotation approach, were able to assign cells into a range of states according to regulatory or pro-inflammatory function and maturation status (effector versus memory). Importantly, they identified a group of potential pathogenicity regulators that co-vary with pro-inflammatory and regulatory expression modules in TH17 cells. Some of the most interesting genes proposed by the analysis were the glycosphingolipid receptor Gpr65, the cell surface regulatory molecule Faim3 (FAS apoptotic inhibitory molecule 3; also known as Toso) and the transcriptional repressor Plzp (promyelocytic leukaemia zinc finger; also known as Zbtb32), which were all shown in functional studies to promote TH17 cell pathogenicity.

... loss of CD5L expression could convert non-pathogenic TH17 cells into pathogenic TH17 cells...

Another of the novel pathogenicity regulators identified in this study was Cd5l, which is described in the second paper (Wang et al.). CD5L expression was associated with non-pathogenic TH17 cells in vitro and in vivo. Consistent with a role for CD5L as a regulator of TH17 cell pathogenicity, Cd5l−/− mice developed more-severe EAE than wild-type mice. In vitro analysis showed that CD5L represses the effector functions but not the differentiation of TH17 cells: effector memory TH17 cells from Cd5l−/− mice make more IL-17 and less IL-10 per cell than wild-type control cells. Moreover, loss of CD5L expression could convert non-pathogenic TH17 cells into pathogenic TH17 cells that induce autoimmunity.

CD5L has previously been shown to regulate lipid metabolism in adipocytes, so the authors profiled the lipidome of TH17 cells with or without CD5L expression. They found that CD5L expression alters the fatty acid composition in TH17 cells, resulting most markedly in an increase in polyunsaturated fatty acids and a decrease in cholesterol metabolites. As cholesterol metabolites, such as oxysterols, can function as ligands for RORγt, the authors tested whether RORγt ligand restriction influences TH17 cell pathogenicity. Indeed, chromatin immunoprecipitation of RORγt showed higher binding to the Il17 and Il23r loci and reduced binding to the Il10 region in Cd5l−/− TH17 cells compared with wild-type cells. Moreover, addition of endogenous RORγt ligand rescued the CD5L-induced suppression of Il17 transcription, together suggesting that lipid metabolism is important in balancing immune protection versus disease induced by TH17 cells.