@article{1101f93fdde44cd89d735906db73b533,
title = "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 (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.",
keywords = "chronic pancreatitis, macrophage, memory T cells, mucosal immunity, pancreas, PD-1, tissue immunity",
author = "Weisberg, {Stuart P.} and Carpenter, {Dustin J.} and Michael Chait and Pranay Dogra and Gartrell-Corrado, {Robyn D.} and Chen, {Andrew X.} and Sean Campbell and Wei Liu and Pooja Saraf and Snyder, {Mark E.} and Masaru Kubota and Danzl, {Nichole M.} and Schrope, {Beth A.} and Raul Rabadan and Yvonne Saenger and Xiaojuan Chen and Farber, {Donna L.}",
note = "Funding Information: This work was supported by a research grant from Bristol-Myers Squibb and by NIH grant AI106697 awarded to D.L.F. S.P.W. was supported by NIH grant K08 DK122130. M.E.S. was supported by NIH grant T32 HL105323, the American Society of Transplantation TIRN award, and a Parker B. Francis Foundation fellowship. P.D. was supported by a CRI Irvington Postdoctoral Fellowship. A.X.C. was supported by NIH grant T32GM007367. R.D.G.-C. was supported by NIH grant KL2TR001874 and Swim Across America. These studies were performed in the CCTI Flow Cytometry Core funded in part through NIH S10 shared instrumentation grants 1S10RR027050 (LSRII), S10OD020056 (Influx), and 5P30DK063608. The Human Studies Core at the Columbia Center for Translational Immunology assisted with patient-informed consent and patient sample procurement. We thank Leonora Peryero and the staff of the immunohistochemistry lab in the CUMC Department of Pathology for technical assistance with performing immunostains on human pancreas samples. We thank Yvette Tanhehco, Shanlong Jiang, and the staff of the CUMC cell therapy lab for technical assistance with pancreas cell processing and clinical sample procurement. We wish to gratefully acknowledge the generosity of the human research subjects who agreed to participate in this study, the organ donor families, and the outstanding efforts of LiveOnNY transplant coordinators and staff for making this study possible. S.P.W. and D.L.F. conceived and designed the study and wrote and edited the paper. X.C. D.J.C. and S.P.W. established a system for isolation of immune cells from pancreas. B.A.S. D.J.C. S.P.W. and N.M.D. designed the study in CP patients and coordinated the acquisition of patient samples. S.C. X.C. P.S. and W.L. performed enzymatic dissociation of human pancreas. S.P.W. designed, collected the samples for, and analyzed the RNA-seq data. M.K. procured organ donor pancreas. S.P.W. and D.J.C. designed the flow cytometry panels and performed acquisition and functional analysis of immune subsets. S.P.W. D.J.C. R.D.G.-C. and Y.S. designed and optimized the multispectral imaging panel. D.J.C, M.C. and S.P.W. performed multispectral imaging acquisition and analysis. R.R. and A.X.C. performed PCF analysis of multispectral images. P.D. D.J.C. M.E.S. and S.P.W. processed donor tissues. P.D. converted cell coordinates provided by inForm software to a map. M.E.S. processed blood samples from healthy donors for RNA-seq. The work described in this study was supported, in part, by a grant from Bristol-Myers Squibb to Donna L. Farber. Funding Information: This work was supported by a research grant from Bristol-Myers Squibb and by NIH grant AI106697 awarded to D.L.F. S.P.W. was supported by NIH grant K08 DK122130 . M.E.S. was supported by NIH grant T32 HL105323 , the American Society of Transplantation TIRN award, and a Parker B. Francis Foundation fellowship. P.D. was supported by a CRI Irvington Postdoctoral Fellowship. A.X.C. was supported by NIH grant T32GM007367 . R.D.G.-C. was supported by NIH grant KL2TR001874 and Swim Across America . These studies were performed in the CCTI Flow Cytometry Core funded in part through NIH S10 shared instrumentation grants 1S10RR027050 (LSRII), S10OD020056 (Influx), and 5P30DK063608 . The Human Studies Core at the Columbia Center for Translational Immunology assisted with patient-informed consent and patient sample procurement. We thank Leonora Peryero and the staff of the immunohistochemistry lab in the CUMC Department of Pathology for technical assistance with performing immunostains on human pancreas samples. We thank Yvette Tanhehco, Shanlong Jiang, and the staff of the CUMC cell therapy lab for technical assistance with pancreas cell processing and clinical sample procurement. We wish to gratefully acknowledge the generosity of the human research subjects who agreed to participate in this study, the organ donor families, and the outstanding efforts of LiveOnNY transplant coordinators and staff for making this study possible. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = dec,
day = "17",
doi = "10.1016/j.celrep.2019.11.056",
language = "English (US)",
volume = "29",
pages = "3916--3932.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}
