T-bet– and STAT4–dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (13), p.4056-4061
• Main Authors: Baumann, Claudia, Bonilla, Weldy V., Fröhlich, Anja, Helmstetter, Caroline, Peine, Michael, Hegazy, Ahmed N., Pinschewer, Daniel D., Löhning, Max
• Format: Article
• Language: English
• Subjects: Animals; Arenaviridae Infections - immunology; Biological Sciences; Bone marrow; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Cell Separation; Cytokines; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Hyaluronan Receptors - metabolism; Immune response; Interferon-gamma - metabolism; Interleukin-33; Interleukins - immunology; L-Selectin - metabolism; Lymphocytes; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C57BL; Rodents; STAT4 Transcription Factor - metabolism; T cell receptors; T-Box Domain Proteins - metabolism; T-Lymphocytes - cytology; Th1 Cells - cytology; Th1 Cells - immunology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1418549112

Significance The alarmin IL-33 amplifies immune responses of Th2 and CD8 ⁺ cytotoxic T cells against invading pathogens; however, little is known about a potential role of IL-33 in Th1 cell responses. This study demonstrates that activated Th1 effector cells transiently express the IL-33 receptor ST2 upon differentiation in vitro and in vivo during viral infection. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2-deficient virus-specific CD4 ⁺ T cells showed impaired expansion and Th1 effector function upon viral infection, indicating a direct impact of IL-33 on antiviral Th1 cell responses. These observations redefine the role of ST2 in Th cell activation, with implications for the design of adjuvants and therapies targeting the IL-33–ST2 pathway. During infection, the release of damage-associated molecular patterns, so-called “alarmins,” orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4 ⁺ T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell–intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4 ⁺ T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.