Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates

Abstract

SummaryHere, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1+ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1+ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1+ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1− cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1+ ILC3s. NRP1+ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.

Dissecting human ILC heterogeneity: more than just three subsets

“…Of note, many markers are expressed differentially among each ILC group. For instance, CD39, CD56, NKp46 or CD161 are expressed heterogeneously by human ILC3 . Similar observations have been carried out for ILC2 cells and expression of NKp30, CD49a or c‐Kit .…”

“…Of note, NKp44 + ILC3 can be divided into two populations based on the expression of neuropilin‐1 (NRP‐1). NRP‐1 + ILC3 produces more cytokines than NRP‐1 − ILC3, and is detected only in lymphoid tissues and inflamed lung tissue …”

The roles for innate lymphoid cells in the human immune system

“…In humans, it has been difficult to identify a distinct LTI population. However, a recent report showed that ILC3 expressing neurophilin 1 (NRP1) are predominantly found near high endothelial venules in lymphoid but not mucosal tissues [51]. NRP1 + ILC3 induce ICAM-1 and VCAM-1 expression on mesenchymal stromal cells, indicative of LTI function.…”

“…NRP1 + ILC3 induce ICAM-1 and VCAM-1 expression on mesenchymal stromal cells, indicative of LTI function. As in the mouse, human NRP1 + ILC3 produce significant levels of IL-22 and IL-17A [51]. Hence, these cells might represent the human LTI.…”

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

“…56 Recently, ILC3s were detected in inflammatory aggregates and near blood vessels in lungs of smokers and COPD patients providing insight into the initiation of smoke-induced ectopic pulmonary lymphoid aggregates ( Figure 1). 15 …”