Journal
JOURNAL OF IMMUNOLOGY
Volume 203, Issue 4, Pages 844-852Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801535
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Funding
- National Institutes of Health (NIH) [R01 AI106791, U24 AI118635, P01 AI35296]
- Helmsley Charitable Trust [2018PG-T1D058]
- Minnesota Partnership for Biotechnology and Medical Genomics MNP [18.01]
- Juvenile Diabetes Research Foundation [3-2014-215]
- Center for Autoimmune Disease Research Pilot Award [UMF0020624]
- Frieda Martha Kunze Fellowship
- NIH [T35 AI118620, R37 AI039560, F30 AI131483, T32 AI007313]
- University of Minnesota Foundation Fund [11724]
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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 auto-antibody 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-Ll 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.
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