Editors' ChoiceGraft-Versus-Host Disease

Losing inhibitions: Expect the unexpected

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Science Translational Medicine  29 Jun 2016:
Vol. 8, Issue 345, pp. 345ec103
DOI: 10.1126/scitranslmed.aag2114

Programmed death 1 (PD-1) is a well-known inhibitory receptor on T cells. Expression of its ligand PD-L1 on cancer cells restrains T cell activation, and this mechanism is reversed upon antibody-mediated blockade of PD-1 or PD-L1, thus generating antitumor immune responses in patients with cancer. Expression of PD-L1 on host tissues has been shown to restrain T cell alloreactivity after adoptive T cell transfer, thus limiting graft-versus-host disease (GVHD) as expected. PD-L1 is also expressed on T cells, but here its function has remained obscure. Given the growing interest in PD-1/PD-L1 blocking antibodies, a detailed mechanistic understanding of this pathway is a high priority.

The starting assumption by Saha and co-authors was that loss of PD-L1 on donor T cells would exacerbate GVHD by unleashing T cell activation. However, T cells from patients with GVHD express high amounts of PD-L1, suggesting that this assumption might be incorrect. Indeed, when T cells from murine donors deficient in PD-L1 were infused into mismatched recipients, GVHD severity was reduced and survival was improved. The authors then performed a comprehensive analysis of T cell phenotype and function, revealing extensive reductions in inflammatory cytokine production, homing receptor expression, and T cell survival along with an altered metabolic program in PD-L1–deficient T cells. These T cells also exhibited a compensatory increase in other, non-PD-1–dependent inhibitory receptors, suggesting an attempt at homeostasis. Overall, the PD-L1–deficient T cells exhibited an inhibited phenotype, but it remains unclear how to reconcile this with the reported function of PD-L1 as an inhibitory receptor ligand.

Thus, despite a laudably thorough description of the PD-L1–deficient T cells, we are left with two major issues. First, the actual mechanism by which the loss of PD-L1 on T cells results in an inhibited phenotype remains undefined, and further investigation will likely uncover important biological interactions. Second, it will be difficult to translate this new observation into a therapy that can benefit patients by reducing GVHD, because the traditional antibody-based blockade of the PD-1/PD-L1 axis would be expected to have immunostimulatory effects (when acting in trans, on tissues other than the donor T cells) as well as immunosuppressive effects (when acting in cis, on the donor T cells themselves).

A. Saha et al., Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J. Clin. Invest. 10.1172/JCI85796 (2016). [Full Text]

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