PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients

• Published in: The Journal of experimental medicine Vol. 214; no. 9; pp. 2523 - 2533
• Main Authors: Zhang, Yuan, Ma, Chi A., Lawrence, Monica G., Break, Timothy J., O’Connell, Michael P., Lyons, Jonathan J., López, Diego B., Barber, John S., Zhao, Yongge, Barber, Daniel L., Freeman, Alexandra F., Holland, Steven M., Lionakis, Michail S., Milner, Joshua D.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.09.2017; The Rockefeller University Press
• Subjects: Adolescent; Adult; Animal models; Animals; Auditory defects; B7-H1 Antigen - physiology; Candidiasis; CD4 antigen; Cell differentiation; Cell Differentiation - physiology; Child; Chronic mucocutaneous candidiasis; Cytokines; Cytokines - physiology; Differentiation (biology); Female; Helper cells; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - physiopathology; Interleukins - physiology; Lymphocytes T; Male; Mice; Mice, Knockout; Middle Aged; Mutation; Patients; PD-1 protein; PD-L1 protein; Phosphorylation; Signal Transduction - physiology; Signaling; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - physiology; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - physiology; Suppressor of Cytokine Signaling 3 Protein - physiology; Th17 Cells - physiology; Up-Regulation; Young Adult
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20161427

Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation—known to inhibit Th17 differentiation in mouse models—was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up-regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling.