Huang, Zak, and Pratumchai et al. showed that in the setting of persistent LCMV infection, type I IFN promoted the short-lived expansion and effector differentiation of CD8+ T cells, while IL-27 promoted the expansion and maintenance of memory-like CXCR5+TCF1+CD8+ T cells, which sustained the T cell response. Type I IFN subdued IL-27 signaling by reducing the expression of the IL-27R subunit GP130. IFNAR1 blockade increased and sustained CXCR5+CD8+ T cell generation, and this was dependent on IL-27, IL-27R, IL-27-mediated activation of STAT1, and upregulation of the transcription factor IRF1, and led to upregulation of prosurvival factors.
Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5(+) TCF1(+) CD8(+) T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5(+) CD8(+) T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8(+) T cells. We found that CD8(+) T cell-intrinsic IL-27 signaling safeguards the ability of TCF1(hi) cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.
Author Info: (1) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (2) Department of Immunology and Microbial Science, The Scripps Research Institute
Author Info: (1) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (2) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (3) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. Department of Chemical Immunology, Leiden University Medical Center, Leiden, Netherlands. (4) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (5) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (6) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (7) National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. (8) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA. (9) Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA teijaro@scripps.edu.
