Impact on Immune Cell Readiness

In their study, the researchers differentiated human iPSCs into macrophages that were then studied in four different states: unstimulated, after 18 hours of stimulation with a signaling molecule interferon-gamma, after five hours infection with Salmonella, and after interferon-gamma stimulation followed by Salmonella infection.

Researchers discovered that genetic variation impacted on the readiness of the immune cells to tackle an infection. Some individuals’ immune cells were ready to deal with the Salmonella infection, whereas other individuals’ macrophages were less ready and took longer to respond.

That level of readiness was due to enhancer priming, where some of the switches were already turned on in the unstimulated cells to facilitate a quicker response. In some cases, the immune cells could be overly eager, which can lead to an inflammatory response associated with immune disorders.

“These results offer important new insights into studying the mechanisms behind infection and disease,” stated Gordon Dougan, Ph.D., of the Wellcome Sanger Institute, another co-author of the study. “If the genetic variant being studied is associated with disease, such as an immune disorder, one needs to be sure of which gene the variant is affecting in order to develop an effective therapy. This may only be visible in a small time-window of the infection.”

The human iPSCs were obtained from the Human Induced Pluripotent Stem Cell Initiative (HipSci). HipSci aims to create a global iPSC resource for the research community by bringing together researchers specializing in genomics, proteomics, cell biology, and clinical genetics.

“A benefit of using stem cells rather than pre-existing blood cells is they’re very flexible, and enabled us to study the effects of stimulation at two different levels,” added Kaur Alasoo, Ph.D., previously of the Wellcome Sanger Institute and now of the University of Tartu, Estonia. “We analyzed which genes in the genome were expressed during each stage of infection, but also looked at the activity of enhancers—the molecular ‘switches’ that controlled the expression of those genes. This novel combination of tools enabled us to see otherwise hidden effects of genetic variation on immune response.”