Identification of self-specific CD4+ T cell subsets resistant to PD-1 blockade
Tijana Martinov, Kristen E. Pauken, Christine Nelson, Justin A. Spanier, James R.
Heffernan, Nathanael L. Sahli, Kevin C. Osum, Marc K. Jenkins, Vaiva Vezys, and Brian T.
Fife
The inhibitory receptor programmed death (PD)-1 and its ligand PD-L1 regulate T cell function
to limit autoimmunity. PD-1 is highly expressed on exhausted T cells, limiting their antiviral or
antitumor activity. Even though PD-1 pathway blockade has gained momentum in cancer
treatment, it is unclear how PD-1/PD-L1 blockade impacts different T cell subsets. We
examined the effects of PD-1 blockade on self-reactive CD4+ T cells in mouse models of varying
autoimmune susceptibilities. We used insulin-peptide/MHC Class II tetramers to track
endogenous insulin-specific CD4+ T cells in diabetes-prone (NOD), and diabetes-resistant (NOR
and B6.g7) mice. PD-1 was expressed at lower levels on insulin-specific cells in diabetesresistant mice compared to cells from NOD mice. Moreover, PD-1 pathway blockade
accelerated autoimmunity in all NOD mice and 30% of NOR mice, but B6.g7 mice remained
protected from disease. By transferring congenically marked islet-specific CD4+ T cells into prediabetic NOD mice, we asked whether anti-PD-L1 reinvigorates anergic cells. Surprisingly,
anergic cells remained functionally blunted compared to effector cells after anti-PD-L1,
suggesting that established anergic cells were not dependent on PD-1 signaling to maintain
their unresponsive state. This work highlights how the differentiation status of a T cell may
predetermine its susceptibility to PD-1 blockade, and influence autoimmunity or antitumor
responses that ensue.
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