Programmed death-1 restrains the germinal center in type 1 diabetes

Tijana Martinov, Linnea A. Swanson, Elise R. Breed, Christopher G. Tucker, Alexander J. Dwyer, Jenna K. Johnson, Jason S. Mitchell, Nathanael L. Sahli, Joseph C. Wilson, Lovejot M. Singh, Kristin A. Hogquist, Justin A. Spanier, Brian T. Fife

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, and although numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production. PD-1 inhibition accelerates autoimmunity in mice, but its role in regulating germinal centers (GC) is controversial. To address the role of PD-1 in the GC reaction in type 1 diabetes, we used tetramers to phenotype insulin-specific CD4+ T and B cells in NOD mice. PD-1 or PD-L1 deficiency, and PD-1 but not PD-L2 blockade, unleashed insulin-specific T follicular helper CD4+ T cells and enhanced their survival. This was concomitant with an increase in GC B cells and augmented insulin autoantibody production. The effect of PD-1 blockade on the GC was reduced when mice were treated with a mAb targeting the insulin peptide:MHC class II complex. This work provides an explanation for autoimmune side effects following PD-1 pathway inhibition and suggests that targeting the self-peptide:MHC class II complex might limit autoimmunity arising from checkpoint blockade.

Original languageEnglish (US)
Pages (from-to)844-852
Number of pages9
JournalJournal of Immunology
Volume203
Issue number4
DOIs
StatePublished - Aug 15 2019

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) R01 AI106791 (to B.T.F.), U24 AI118635 (to B.T.F.), and P01 AI35296 (to B.T.F. and K.A.H.), Helmsley Charitable Trust 2018PG-T1D058 (to B.T.F.), Minnesota Partnership for Biotechnology and Medical Genomics MNP#18.01 (to B.T.F.), Juvenile Diabetes Research Foundation 3-2014-215 (to J.A.S.), Center for Autoimmune Disease Research Pilot Award UMF0020624 (to J.A.S.), a Frieda Martha Kunze Fellowship (to T.M.), NIH T35 AI118620 (to L.A.S.), R37 AI039560 (to K.A.H.), F30 AI131483 (to E.R.B.), and T32 AI007313 (to E.R.B. and C.G.T.), and University of Minnesota Foundation Fund 11724 (Diabetes Cure Research Using Immune Regulation and Tolerance).

Publisher Copyright:
© 2019 by The American Association of Immunologists, Inc.

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