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

34 Scopus citations

Abstract

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
Volume194
Issue number8
DOIs
StatePublished - Apr 15 2015

Bibliographical note

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

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