T cells, together with B cells, are the workhorses of the adaptive immune response. And although some cells that are associated with the innate immune response can take on adaptive properties, it has been thought that T and B cells tend to stay in their adaptive lane.

Now, a new study shows that certain human T cells express gasdermin E which helps the release of the cytokine interleukin (IL)-1α. This new role for T cells was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome. This gasdermin E pore formation in T cells is a mechanism of unconventional cytokine release. The research reveals several previously unknown properties of these immune cells that are relevant regarding both autoimmune diseases as well as fighting fungal infections.

This research is published in Nature Immunology, in the paper, “Human TH17 cells engage gasdermin E pores to release IL-1α upon NLRP3 inflammasome activation.

“We found a cytokine in a subset of T helper cells, the TH17 cells, that was previously known to be part of the innate immune system,” explained Christina Zielinski, MD, chair of infection immunology at the Leibniz Institute for Natural Product Research and Infection Biology at the Hans Knöll Institute. The cytokine, IL-1α, is strongly pro-inflammatory. “It is a signal molecule for danger. Even the smallest amounts are enough to trigger fever,” Zielinski said. It is thought to be involved in autoimmune diseases such as rheumatoid arthritis in children.

“We didn’t know how IL-1α is made in T cells and how it gets out of the cells,” said Ying-Yin Chao, PhD, who worked in the Zielinski lab until 2021.

To investigate the heterogeneity of the human TH17 cell subset, and to reveal distinct functions and their molecular control, the team wrote that they performed single-cell RNA-sequencing (scRNA-seq) of activated human TH17 cells which had been isolated from peripheral blood according to their unique expression of chemokine receptor surface markers.

The researchers found that IL-1α, unlike other cytokines, is produced by a multiprotein complex known as the inflammasome in T cells. This protein complex has very different roles in other cells. “Until now, it was unknown that human T cells had such an inflammasome and that it could be repurposed to produce IL-1α,” Zielinski said.

Equally unexpected was the transport pathway out of the cells. “We found via knockout experiments that gasdermin E is responsible for this,” explained Alisa Puhach, a PhD student in the lab. This molecule forms pores in cell membranes. Such a mechanism for the export of inflammatory mediators from T cells was previously unknown.

The release of the cytokine IL-1α appears to be restricted to a subset of TH17 cells; other T helper cell types do not produce it. “TH17 cells play an important role in fungal infections,” Zielinski said. The team, therefore, investigated whether IL-1α is also involved and was able to show that mainly TH17 cells with antigen specificity for the infectious yeast C. albicans secrete the cytokine. This subset of TH17 cells is therefore likely to be relevant for the defense against infections with the common yeast fungus.

In further studies, the researchers now want to find out in which other diseases the pore-forming gasdermin E plays a role in T cells.

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