A Membrane Lipid Signature Unravels the Dynamic Landscape of Group 1 ILCs across the Health-Disease Continuum

In an era where the established lines between cell identities are blurred by intra-lineage plasticity, distinguishing between stable and transitional states becomes imperative. This challenge is particularly pronounced within the Group 1 ILC lineage, where the similarity and plasticity between NK cells and ILC1s obscure their classification and the assignment of their unique contributions to immune regulation. This study exploits the unique property of AsGM1—a membrane lipid associated with cytotoxic attributes absent in ILC1s—as a definitive criterion to distinguish between these cells. By prioritizing cytotoxic potential as the cardinal differentiator, the strategic use of this glycosphingolipid signature achieved precise delineation of the heterogenity of Group 1 ILCs across tissues. This capability extends beyond steady-state classifications, adeptly capturing the binary classification of NK cells and ILC1s during acute liver injury. By leveraging two established models of NK-to-ILC1 plasticity driven by TGFβ in endocrine tissues and Toxoplasma gondii infection, we demonstrate the stability of the AsGM1 signature during this reprogramming, which sharply contrasts with the loss of Eomes. The early detection of the AsGM1 signature at the immature NK (iNK) stage, preceding Eomes, and its stability, unaffected by transcriptional reprogramming that typically alters Eomes, position AsGM1 as a unique, site-agnostic marker for fate mapping NK-to-ILC1 plasticity. This provides a powerful tool to explore the expanding heterogeneity within the Group 1 ILC landscape, effectively transcending the ambiguity inherent to the NK-to-ILC1 continuum.