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


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.

SUBMITTER: Pauken KE 

PROVIDER: S-EPMC4390507 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Pauken Kristen E KE   Nelson Christine E CE   Martinov Tijana T   Spanier Justin A JA   Heffernan James R JR   Sahli Nathanael L NL   Quarnstrom Clare F CF   Osum Kevin C KC   Schenkel Jason M JM   Jenkins Marc K MK   Blazar Bruce R BR   Vezys Vaiva V   Fife Brian T BT  

Journal of immunology (Baltimore, Md. : 1950) 20150313 8


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 blocka  ...[more]

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