Cutting edge: Identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade

Kristen E. Pauken, Christine E. Nelson, Tijana Martinov, Justin A. Spanier, James R. Heffernan, Nathanael L. Sahli, Clare F. Quarnstrom, Kevin C. Osum, Jason M. Schenkel, Marc K. Jenkins, Bruce R. Blazar, Vaiva Vezys, Brian T. Fife

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Programmed death-1 (PD-1) promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD ligand 1 (PD-L1) regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune-susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in type 1 diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additionally, PD-L1 was critical for induction, but not maintenance, of CD8 T cell intestinal tolerance. PD-L1 blockade enhanced functionality of effector T cells, whereas established tolerant or anergic T cells were not dependent on PD-1/PD-L1 signaling to remain unresponsive. This highlights the existence of Ag-experienced T cell subsets that do not rely on PD-1/PD-L1 regulation. These findings illustrate how positive treatment outcomes and autoimmunity development during PD-1/PD-L1 inhibition are linked to the differentiation state of a T cell.

Original languageEnglish (US)
Pages (from-to)3551-3555
Number of pages5
JournalJournal of Immunology
Issue number8
StatePublished - Apr 15 2015

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Copyright © 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00.


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