Dengue viruses (DENV) are the mosquito-borne viruses of greatest global public health importance. DENV circulate as four serotypes with significant immunologic cross-reactivity that does not provide protection from secondary infection with heterologous serotypes. The strong association of severe dengue illness, dengue hemorrhagic fever (DHF), with heterologous secondary infection and high cytokine levels has led to a prevailing view that DHF is immunologically mediated. In vitro studies of DENV-specific T lymphocytes, clinical studies of acute DENV infection, and immunologic studies in mouse models have provided evidence that in heterologous secondary DENV infection, there is preferential activation of memory T lymphocytes with lower avidity for the infecting virus ('original antigenic sin') resulting in altered T-cell functional responses. In the setting of host genetic predisposition and high level viremia, with resulting high antigenic burden, we postulate that a skewed T-cell cytokine response leads to plasma leakage in DHF. A better understanding of the immune responses associated with increased or decreased risk for DHF will be of immense value for the clinical studies of candidate multivalent DENV vaccines anticipated to take place in the next several years.

Dengue remains one the most important mosquito borne disease worldwide. Infection with one of the serologically related dengue viruses (DENV) can lead to a wide range of clinical manifestations and severity. Severe dengue is characterized by plasma leakage and abnormal bleeding that can lead to shock and death. There is currently no specific treatment for severe dengue due to gaps in understanding of the underlying mechanisms. The transient period of vascular leakage is usually followed by a rapid recovery and is suggestive of the effects of short lived biological mediators. Both the innate and the adaptive immune systems are activated in severe dengue and contribute to the cytokine production. We discuss the immunological events elicited during a DENV infection and identify candidate cytokines that may play a key role in the severe manifestations of dengue and possible interventions.

Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro–differentiated Stat6+/+ antigen-specific Th2 cells were adoptively transferred into naive Stat6−/− and Stat6+/+ mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6+/+ mice, were dramatically absent in Stat6−/− mice that received Stat6+/+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.