Editors' ChoiceImmunology

Good for allergies, bad for lung metastasis

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Science Signaling  06 Sep 2016:
Vol. 9, Issue 444, pp. ec204
DOI: 10.1126/scisignal.aai9314

The lung is continually exposed to the external environment, making it necessary to tightly regulate the activity of effector T cells in the lung to prevent inappropriate responses to innocuous foreign antigens. Suppression of effector T cells occurs through regulatory T (Treg) cells that are derived from the thymus (tTreg cells) or that are induced in the periphery (iTreg cells). Under normal oxygen conditions, and particularly in the highly oxygenated environment of the lung, the prolyl hydroxylase (PHD) family of oxygen sensors prevents transcriptional responses to hypoxia by keeping the abundance of the α subunits of hypoxia-inducible factors (HIFs) low. HIFs trigger the production of the proinflammatory cytokine interferon-γ (IFN-γ) in Treg cells, leading Clever et al. to investigate the role of the PHDs in T cells in the lung. Compared with their wild-type counterparts, mice with T cell–specific deficiency in all three PHD isoforms (PHD-tKO) developed diffuse alveolar hemorrhage, had more CD4+ and CD8+ T cells in the lung, and had fewer iTreg cells in the lung. Production of IFN-γ from pulmonary CD4+ and CD8+ T cells was increased. The lungs of wild-type mice that had been sensitized and challenged with house dust mite extract had more Treg cells and T helper 2 (TH2) cells, which promote B cell proliferation and are implicated in the development of asthma. In contrast, the lungs of similarly sensitized PHD-tKO mice had more IFN-γ–positive TH1 cells, which promote the proliferation of cytotoxic T cells, fewer iTreg cells, and showed signs of inflammation and associated pathology, such as alveolar hemorrhage. When exposed to transforming growth factor–β, a cytokine that promotes Treg cell differentiation, naïve CD4+ T cells from wild-type mice differentiated into Treg cells, whereas those from PHD-tKO mice differentiated into TH1 cells and produced more IFN-γ. When exposed to high oxygen concentrations (20%), wild-type mouse and human CD4+ T cells tended to differentiate into Treg cells, an effect that was blocked by the PHD inhibitor dimethyloxalylglycine (DMOG). Under normal oxygen conditions, DMOG promoted the differentiation of mouse CD4+ T cells into TH1 cells, an effect that did not occur in cells deficient in HIF-1α and HIF-2α. The authors speculated that infiltrating tumor cells may evade immune surveillance in the lung because the antigens on these cells might resemble innocuous foreign antigens and do not relieve the suppression of Teff cell function by Treg cells. Whereas the growth of tumors formed from subcutaneously injected B16 mouse melanoma cells was similar in wild-type mice and PHD-tKO mice, B16 cells injected in the tail vein more readily colonized the lungs of wild-type mice compared with the lungs of the PHD-tKO mice. The reduction in the tumor burden in the lungs of PHD-tKO mice was abrogated when an IFN-γ–neutralizing antibody was coinjected with the B16 cells. DMOG treatment of CD4+T cells before adoptive transfer into mice with lung tumors formed from B16 cells improved the clearance of these tumors. Thus, the PHD family of oxygen sensors limits reactivity to innocuous foreign antigens but also antitumor immunity, and inhibiting PHDs may improve the success of adoptive cell transfer cancer immunotherapy.

D. Clever, R. Roychoudhuri, M. G. Constantinides, M. H. Askenase, M. Sukumar, C. A. Klebanoff, R. L. Eil, H. D. Hickman, Z. Yu, J. H. Pan, D. C. Palmer, A. T. Phan, J. Goulding, L. Gattinoni, A. W. Goldrath, Y. Belkaid, N. P. Restifo, Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166, 1117–1131 (2016). [PubMed]

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