Extended Data Fig. 10: Proposed model of cell-cell interactions in healthy lean and obese human WAT.

In lean WAT, IL-15 expression from cDC2A coupled with IL-15RA expression from APCs may support the viability of IL-15RB-expressing ILCs and NK cell populations. CSF1 (M-CSF) expression from APCs and IL-13 from ILC2s likely drives the Mo-1 transition to PVMs, while CSF2 from APCs may support dendritic cell homeostasis. cDC2A-derived CD200 could suppress ILC activation at steady-state. TGFβ1, PDGF, AREG, and GAS6 signaling from dendritic cells and PVM to APCs may promote tissue homeostasis. During obesity, IL-23 from an unknown source could drive the differentiation and accumulation of WAT ILC3s from ILCP-like cells. cDC2B-derived IL-18 and potentially IL-12 might stimulate the production of IFNγ by trNK and ILC1 subsets and contribute to the development of LAM from PVM. Increased CCL2 production from hypoxia-sensing PVM and SMC could recruit circulating Mo-1 into the WAT where MIF, LIF, and IFN-γ signaling from ILCs and NKs, as well as IL-1β, OSM and TNF-α signaling from IM, LAM, and cDC2B could polarize Mo-1 to the IM fate. trNK production of TNFSF14 (LIGHT) may further promote activation of cDC2B and IM. Together, these interactions suggest a cell type specific positive feedback loop whereby accumulation and polarization of WAT-resident lymphoid and myeloid cell types potentiate inflammation during human obesity.