Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway.
The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)-programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte-associated antigen 4 pathway. Anti-PD-1 and anti-PD-L1, but not anti-PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1-PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1-PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1-PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.
Fife
Brian T
BT
UCSF Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, and Transplantation Research Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
Guleria
Indira
I
Gubbels Bupp
Melanie
M
Eagar
Todd N
TN
Tang
Qizhi
Q
Bour-Jordan
Helene
H
Yagita
Hideo
H
Azuma
Miyuki
M
Sayegh
Mohamed H
MH
Bluestone
Jeffrey A
JA
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D060890:B7-H1 Antigen; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D007108:Immune Tolerance; D007328:Insulin / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D012074:Remission Induction; D015398:Signal Transduction / Q000502:physiology*
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007328:Insulin; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor