SkinChronicles, No 6, April 2025, by Attila Gábor Szöllősi

Langerhans cells are, in my opinion, one of the most fascinating cells in the human body. They are cells positioned at both physical and conceptual boundaries. In the literal sense because they populate the outermost layer of the skin and act as immune sentinels. Figuratively they also exist in the grey area between cell types as we define them. Ontogenetically they are most similar to resident macrophages, since they originate from embryonic precursors and are independent of adult bone marrow-derived cells in the steady state, due to their self-renewal capability. Functionally, they behave as dendritic cells, which was reported 40 years ago (to the day) by Schuler and Steinman in their landmark paper. Since then, they have been shown to not only activate inflammatory T cell responses but also to contribute to immune tolerance. A recent study in JID innovations by Oka et al. provides compelling evidence that this tolerogenic function extends beyond their migratory capacity. Through immunofluorescence analysis (and, surprisingly, no “big data”) they demonstrated that LCs expressing high levels of HLA-II, CD86, and PD-L2 are in direct contact with tissue-resident memory T cells, and CTLA-4+ Tregs, indicating an axis of peripheral tolerance in steady-state conditions. Furthermore, their findings suggest that immune checkpoint blockade can disrupt LC-T cell contacts, potentially providing an explanation for some cutaneous immune-related adverse events. As a researcher focused on Langerhans cells, impactful results such as these show that there is still much to explore, even on our favorite cells.

Papers:

1. Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med. 1985 Mar 1;161(3):526-46. doi: 10.1084/jem.161.3.526. PMID: 3871837; PMCID: PMC2187584.
2. Oka T, Hasegawa T, Lee T, Oliver-Garcia VS, Mortaja M, Azin M, Horiba S, Smith SS, Khattab S, Trerice KE, Chen ST, Semenov YR, Demehri S. Langerhans Cells Directly Interact with Resident T Cells in the Human Epidermis. JID Innov. 2024 Nov 7;5(1):100324. doi: 10.1016/j.xjidi.2024.100324. PMID: 39803386; PMCID: PMC11720605.