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

Stuart P. Weisberg, Dustin J. Carpenter, Michael Chait, Pranay Dogra, Robyn D. Gartrell-Corrado, Andrew X. Chen, Sean Campbell, Wei Liu, Pooja Saraf, Mark E. Snyder, Masaru Kubota, Nichole M. Danzl, Beth A. Schrope, Raul Rabadan, Yvonne Saenger, Xiaojuan Chen, Donna L. Farber

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3916-3932.e5
JournalCell Reports
Volume29
Issue number12
DOIs
StatePublished - Dec 17 2019
Externally publishedYes

Keywords

  • chronic pancreatitis
  • macrophage
  • memory T cells
  • mucosal immunity
  • pancreas
  • PD-1
  • tissue immunity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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