A Murine Intestinal Intraepithelial NKp46-Negative Innate Lymphoid Cell Population Characterized by Group 1 Properties

Abstract

The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα T lymphocytes, and CD49a liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46CD8ααLy49E cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.

Diverse developmental pathways of intestinal intraepithelial lymphocytes

“…In addition to ILC1s, several populations of ILC1-like cells are present in the intestinal epithelium and may be involved in regulating intestinal immune responses 6,83,84 . Notably, CD8αα + innate IELs are an ILC1-like, non-T cell IEL population that is developmentally distinct from unconventional TCRαβ + and TCRγδ + IELs; they do not require ID2 for their development but express αEβ7 integrin and a single type of NK cell receptor, lymphocyte antigen 49E (LY49E; also known as KLRA5) 6,83 .…”

“…Notably, CD8αα + innate IELs are an ILC1-like, non-T cell IEL population that is developmentally distinct from unconventional TCRαβ + and TCRγδ + IELs; they do not require ID2 for their development but express αEβ7 integrin and a single type of NK cell receptor, lymphocyte antigen 49E (LY49E; also known as KLRA5) 6,83 . Strikingly, there is a reduced frequency of CD8αα + innate IELs in TL-deficient mice, suggesting an interaction between CD8αα and TL in these cells 6 .…”

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…Indeed, T‐bet‐dependent ILC1s are able to control T. gondii infections by their release of IFN‐γ and TNF‐α . An additional T‐bet‐dependent population of intraepithelial lymphocytes with an ILC1 profile has been reported recently . These NKp46 − CD8αα − Ly49E + IELs express IFN‐γ upon T. gondii infection, and thereby promote the type 1 immune response to eliminate T. gondii .…”

“…13 An additional T-bet-dependent population of intraepithelial lymphocytes with an ILC1 profile has been reported recently. 101 These NKp46 À CD8aa À Ly49E + IELs express IFN-c upon T. gondii infection, and thereby promote the type 1 immune response to eliminate T. gondii. A recent report identified plasticity of NK cells to ILC1s using Eomes-fate-map mice in T. gondii infection highlighting how closely related these populations are.…”

Innate CD8αα+cells and osteopontin promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation

“…iCD8α cells possess a chemokine and cytokine signature, antigen processing capabilities, and other functions like bacteria uptake, that suggest that these cells are important during early immune responses [11]. Other TCR neg IEL resemble innate lymphoid cells (ILC) with differential expression of the natural cytotoxicity receptor NKp46 [12–14]. Although their function is not completely understood, NKp46 + NK1.1 + IEL have been shown to promote disease development in the anti-CD40 model of colitis [12].…”