Non-recirculating tissue-resident memory T cells (TRMs) 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-1hi TRMs, which are phenotypically, functionally, and transcriptionally distinct compared to TRMs in neighboring jejunum and lymph node sites. Pancreas TRMs 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, TRMs 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. Display omitted •The human pancreas contains CD8+ TRMs exhibiting tissue-specific molecular signatures•Pancreas TRMs express high levels of PD-1 yet maintain strong effector function•During homeostasis, pancreas TRMs are regulated by PD-L1+ tissue macrophages•In chronic pancreatitis, TRM PD-1 levels and PD-L1+ macrophage density are reduced Non-recirculating tissue-resident memory T cells (TRMs) mediate immune responses in non-lymphoid tissues. Using a human organ donor tissue resource, Weisberg et al. reveal that PD-1hi pancreas TRMs are regulated by PD-L1+ macrophages during homeostasis. Comparison with chronic pancreatitis patient samples shows how pancreas TRM regulation is altered during inflammation.