Pathway for Langerhans cell skin/immune system communication identified

Immune cells, pictured here in bright teal, occupy the epithelial layers between the skin surface and its stem cells and act as a system regulator. (Photo by: Fuchs lab)

Researchers have discovered a regulatory circuit connecting the skin surface to stem cells via Langerhans immune cells (LCs) that act as immune system regulators. They published their results in Science.

This circuit acts like a “rheostat” that continuously fine-tunes the stem cells’ response to the environment at the skin surface, said the study’s first author, Anita Gola, PhD, in a press release.

Dr. Gola is a research associate in the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development at Rockefeller University, New York.

“Langerhans cells pick up signals from microbes on the skin surface and, through chemical messaging, signal to stem cells whether they need to produce new stem cells or direct cells to differentiate,” she said.

“Essentially, Langerhans cells act as liaisons to regulate host-microbe interactions, while joining forces with the stem cells to maintain the integrity and antimicrobial peptide production of the skin’s barrier,” said senior author Elaine Fuchs, PhD. Dr. Fuchs heads the Robin Chemers Neustein Laboratory.

The research team aimed to understand the communication system linking epidermal stem cells to signals coming from microbes on the body surface, which enable dynamic responses to ever-changing environmental factors.

They suspected the signalling network involved nearby cells in the local “niche”—a kind of cellular and physical neighbourhood. Within this niche in mouse skin there were only two potential candidates: dendritic epithelial T cells (DETCs), a type of specialized lymphocyte, and LCs, a classic antigen-presenting cell, known to be a central player in driving adaptive immune responses in lymph nodes.

Dr. Fuchs and her colleagues leaned toward LCs, which concentrate in vulnerable barrier areas such as the skin, mouth, and nose. “We know that macrophages in general are highly sensitive to their local environment and often have embedded functions that maintain their niches, so we wondered whether Langerhans cells, which spend their lives in sustained contact with epidermal stem cells and can extend their dendrites right through the skin’s epithelial layers, might have additional, stem cell regulatory roles beyond their well-appreciated immunological ones,” said Dr. Gola.

Using genetic LC knockout approaches in a series of in vivo experiments, the Fuchs lab found that animals lacking LCs showed increased epidermal stem-cell proliferation and differentiation.

Dr. Gola said the finding “suggested that the stem cell compartment wasn’t behaving exactly as it should in a homeostatic condition.”

“That was our first smoking gun.”

By probing gene expression in these cells, they found a gene called Ptgs1 was uniquely enriched in LCs when compared to all other skin resident immune cells. The gene codes for the enzyme COX-1, which is essential for producing prostaglandins, a class of hormone-like lipid mediators involved in many cellular functions. In LCs, high COX-1 expression led to robust production of a prostaglandin called PGE2. They then discovered that epidermal stem cells have only one prostaglandin receptor—EP4, and it’s the one specific for PGE2.

Further experiments revealed what happens when there isn’t enough PGE2 for the stem cells: “Without this brake on proliferation, stem cell proliferation increases,” said Dr. Fuchs.

“Their progeny don’t completely finish differentiating before reaching the skin surface, which means that they can’t perform quite as well the tasks they’re supposed to do. It’s like sending in a team of amateurs to do work that requires professional expertise.”

That incomplete development led to specific problems. Immature epithelial cells had extreme responses to benign bacteria that would normally reside on mouse skin without issue.

The team also observed structural weakening of the skin barrier, an overgrowth of different types of native bacteria, and a decrease in the amount of antimicrobial peptides that the skin should make to maintain a healthy microbiota.

The presence of LCs prevented these negative outcomes through suppressing a signalling pathway associated with cell division and promoting the production of differentiated cells.

“We think that there is some redundancy in the system, so it could be that this COX-1 prostaglandin regulator integrates multiple signals upstream,” Dr. Gola said.

The researchers theorize that because the cycle of response and reset is so essential to protecting the skin barrier, this system may integrate a number of signals to maintain local skin fitness. Looking forward, the Fuchs lab is planning to now explore how Langerhans cells respond to negative inputs such as pathogenic bacteria and inflammation.