Editors' ChoiceImmunology

Revisiting PD-1 signaling

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Science Signaling  17 Apr 2018:
Vol. 11, Issue 526, eaat8704
DOI: 10.1126/scisignal.aat8704

The protective effect of anti-PD1 therapy in cancer may not require the phosphatase Ptpn11.

T cell exhaustion results from chronic antigen stimulation during prolonged viral infections or cancer. In these diseases, progressively increased expression of inhibitory receptors, including programed cell death 1 (PD-1), correlates with advancing T cell dysfunction. Therapies that block PD-1 can augment patient T cell responses to cancer and restore the function of exhausted virus-specific T cells in mice. Activation of PD-1 on T cells dampens signaling by the costimulatory receptor CD28 in vitro by recruiting the phosphatase Ptpn11 (also known as Shp-2). However, Rota et al. found that Ptpn11 was not required for PD-1–mediated effects in mice. Unlike mice with PD-1–deficient T cells, mice with Ptpn11-deficient T cells did not develop excessive immunopathology after chronic viral infection. Additionally, deletion of Ptpn11 in T cells did not inhibit the efficacy of anti–PD1 tumor therapy. These data suggest that there may be Ptpn11-independent pathways of PD-1 signaling that inhibit T cell function. Furthermore, these data suggest that the signaling mechanisms of this clinical cancer immunotherapy deserve further scrutiny in primary T cell populations.

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