Abstract
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.
Highlights
During infection, the release of damage-associated molecular patterns, so-called “alarmins,” orchestrates the immune response
ST2 deficiency of LCMVspecific CD4+ T cells resulted in impaired effector Th1 cell differentiation with substantially reduced cell expansion, impaired antiviral cytokine production, and little virus-induced T-cell–mediated immunopathology
We have shown that the IL-33 receptor ST2 is induced on Th1 effector cells upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection
Summary
The release of damage-associated molecular patterns, so-called “alarmins,” orchestrates the immune response. ST2-deficient virus-specific CD4+ T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches Intercellular signaling molecules, such as cytokines and damageassociated molecular patterns (DAMPs), are essential for the induction and amplification of immune responses. DAMPs are multifunctional host proteins that indicate tissue damage They are referred to as alarmins, because they serve as early warning signals to activate innate and adaptive immune responses [1]. IL-33 acts directly on CD4+ T cells during infection to enhance antiviral effector Th1 cell responses
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