Autoimmune rheumatologic diseases
Obtaining TH1 memory cells from human donors at the scale needed for high-throughput functional-genomic and pharmacological screens for identification of new drug targets is a challenge. In vitro polarization of naïve human CD4 T cells to IFNγ- and TNFα-producing TH1 cells allows for the generation of large numbers of cells; however, whether these in vitro conditions mimic global transcriptional activation programs of in-vivo-generated TH1 cells is unknown. Using RNA-seq, we have generated global transcriptional profiles of in-vitro-generated TH1 cells and in-vivo-generated CD4 TH1 and TH2 memory cells from the peripheral blood of healthy human donors (with the latter isolated based on their differential expression of chemokine receptors), under both steady state conditions and upon acute TCR stimulation. For in-vivo-generated TH1 and TH2 cells, global transcriptional activation profiles were highly consistent and a common activation signature is apparent. We find that there is a shared transcriptional metabolic signature of activation between in-vivo-generated TH1 and TH2 cells that includes oxidative phosphorylation, the TCA cycle and multiple amino acid pathways. Furthermore, we demonstrate that the transcriptional activation profiles are strongly positively correlated between TH1 cells generated in vivo and TH1 cells generated in vitro, suggesting that TCR stimulation of in-vitro-generated TH1 cells executes a transcriptional program that mimics that of their in-vivo-generated counterparts. Our data support the use of in vitro differentiated human T cells as a model system for discovery of novel immunometabolism targets.