Columbia University - Department of Microbiology and Immunology; Columbia University - Columbia Center for Translational Immunology; Columbia University, Columbia University Medical Center, Department of Surgery
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-1hi 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.
Weisberg, Stuart and Carpenter, Dustin J. and Chait, Michael and Dogra, Pranay and Gartrell, Robyn D. and Chen, Andrew X. and Campbell, Sean and Liu, Wei and Saraf, Pooja and Snyder, Mark E. and Kubota, Masaru and Danzl, Nichole M. and Schrope, Beth A. and Rabadan, Raul and Saenger, Yvonne and Chen, Xiaojuan and Farber, Donna, Tissue-Resident Memory T Cells Mediate Immune Homeostasis in the Human Pancreas Through the PD-1/PD-L1 Pathway (August 31, 2019). Available at SSRN: https://ssrn.com/abstract=3445675 or http://dx.doi.org/10.2139/ssrn.3445675
This version of the paper has not been formally peer reviewed.
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