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

60 Pages Posted: 4 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Stuart Weisberg

Stuart Weisberg

Columbia University

Dustin J. Carpenter

Columbia University

Michael Chait

Columbia University

Pranay Dogra

Columbia University

Robyn D. Gartrell-Corrado

Columbia University

Andrew X. Chen

Columbia University - Department of Systems Biology

Sean Campbell

Columbia University - Columbia Center for Translational Immunology

Wei Liu

Columbia University - Columbia Center for Translational Immunology

Pooja Saraf

Columbia University

Mark E. Snyder

Columbia University - Department of Medicine

Masaru Kubota

Columbia University - Department of Surgery

Nichole M. Danzl

Columbia University - Department of Medicine

Beth A. Schrope

Columbia University

Raul Rabadan

Columbia University - Department of Systems Biology; Columbia University - Department of Biomedical Informatics

Yvonne Saenger

Columbia University

Xiaojuan Chen

Columbia University - Columbia Center for Translational Immunology

Donna Farber

Columbia University - Columbia Center for Translational Immunology; Columbia University - Department of Microbiology and Immunology; Columbia University, Columbia University Medical Center, Department of Surgery

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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-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.

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

Suggested Citation

Weisberg, Stuart and Carpenter, Dustin J. and Chait, Michael and Dogra, Pranay and Gartrell-Corrado, 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). CELL-REPORTS-D-19-03309. Available at SSRN: https://ssrn.com/abstract=3445675 or http://dx.doi.org/10.2139/ssrn.3445675
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Stuart Weisberg

Columbia University

3022 Broadway
New York, NY 10027
United States

Dustin J. Carpenter

Columbia University

3022 Broadway
New York, NY 10027
United States

Michael Chait

Columbia University

3022 Broadway
New York, NY 10027
United States

Pranay Dogra

Columbia University

Robyn D. Gartrell-Corrado

Columbia University

3022 Broadway
New York, NY 10027
United States

Andrew X. Chen

Columbia University - Department of Systems Biology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Sean Campbell

Columbia University - Columbia Center for Translational Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Wei Liu

Columbia University - Columbia Center for Translational Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Pooja Saraf

Columbia University

3022 Broadway
New York, NY 10027
United States

Mark E. Snyder

Columbia University - Department of Medicine

630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Masaru Kubota

Columbia University - Department of Surgery ( email )

New York, NY
United States

Nichole M. Danzl

Columbia University - Department of Medicine

630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Beth A. Schrope

Columbia University

3022 Broadway
New York, NY 10027
United States

Raul Rabadan

Columbia University - Department of Systems Biology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Columbia University - Department of Biomedical Informatics

3022 Broadway
New York, NY 10027
United States

Yvonne Saenger

Columbia University

3022 Broadway
New York, NY 10027
United States

Xiaojuan Chen

Columbia University - Columbia Center for Translational Immunology ( email )

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Donna Farber (Contact Author)

Columbia University - Columbia Center for Translational Immunology ( email )

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Columbia University - Department of Microbiology and Immunology ( email )

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Columbia University, Columbia University Medical Center, Department of Surgery ( email )

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

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