Tissue-Resident Memory T Cells Mediate Immune Homeostasis in the Human Pancreas Through the PD-1/PD-L1 Pathway

Abstract

Non-recirculating tissue resident memory T-cells (TRM) are the predominant T cell subset in diverse tissue sites where they mediate protective immune responses in situ. Here, we reveal a role for TRM in maintaining immune homeostasis in the human pancreas, through interactions with resident macrophages and the PD-1/PD-L1 inhibitory pathway. Using tissues obtained from organ donors, we identify that pancreas T cells comprise CD8⁺PD-1^hi TRM, which are phenotypically, functionally and transcriptionally distinct compared to TRM in neighboring jejunum and lymph node sites. Pancreas TRM cluster with resident macrophages throughout the exocrine areas; TRM effector functions are enhanced by macrophage-derived co-stimulation and attenuated by the PD-1/PD-L1 pathways. Conversely, in samples from chronic pancreatitis, TRM exhibit reduced PD-1 expression and reduced interactions with macrophages. These findings suggest important roles for PD-1 and TRM-macrophage interactions in controlling tissue homeostasis and immune dysfunctions underlying inflammatory disease, with important implications for PD-1-based immunotherapies.

Keywords: Memory T-cells, Pancreas, Chronic Pancreatitis, Tissue immunity, Mucosal Immunity, PD-1, Tissue Macrophage