Obesity promotes an immunogenic landscape of macrophage T cell interaction in human pancreas.

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Presentation Time: 05:30 PM - 05:45 PM
Abstract ID: 5491 - B

Presenting Author:
Kranthi Kiran Kishore Tanagala , Associate Research Scientist at Columbia Univ. Irving Med. Ctr.

Abstract:

Pancreas plays a central role in digestion and metabolism and is highly sensitive to obesity, which causes chronic inflammation and raises the risk for pancreatitis and pancreatic cancer. We performed studies to elucidate macrophage and T cell dynamics in pancreas of obese and non-obese human organ donors. Multiplexed imaging of pancreas tissue and analysis of cellular neighborhoods (n=32) showed that higher body mass index (BMI) significantly correlates with increased T cell and macrophage-rich clusters in exocrine pancreas. The T cells predominantly comprise clonally expanded cytotoxic TRMs. Multiomic single cell analysis (n=5) of the myeloid compartment revealed a distinct population of CD11c^hi macrophages with pro-inflammatory antigen presenting cell signatures. Cell sorting and functional analysis in-vitro (n=5-10) showed that CD11c^hi macrophages promote T cell activation and induce pro-inflammatory T cell effector states (TNF-α⁺, granzyme B⁺) via co-stimulation molecules (CD86, CD58) and secretion of cytokines (IL-1β, IL-18). The CD11c^hi macrophages occupy distinct niches in pancreas, surrounding CK19-expressing ductal cells, and show a high rate of proliferation in situ. Higher BMI correlates with greater T cell interaction with CD11c^hi macrophages in situ. Collectively, these studies elucidate how obesity perturbs macrophage-T cell crosstalk to produce a pancreas immune landscape that fosters chronic inflammation and raises the risk for pancreatic diseases.