CD4+ T helper cells acquire effector phenotypes that promote specialized inflammatory responses. We show that the ETS family transcription factor, PU.1 was required for the development of an interleukin 9 (IL-9)-secreting subset of TH cells. Decreasing PU.1 expression either by conditional deletion in murine T cells or siRNA in human T cells impaired IL-9 production, while ectopic PU.1 expression promoted IL-9 production. Mice with PU.1-deficient T cells developed normal TH2 responses in vivo, but exhibited attenuated allergic pulmonary inflammation corresponding to decreased Il9 and chemokine expression in peripheral T cells and in lungs as compared to wild-type mice. Together, these data suggest a critical role for PU.1 in generating the TH9 phenotype and in the development of allergic inflammation.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine important for the initiation and development of T helper (Th2) cell-mediated allergic inflammation. In this study, we identified a positive association between interleukin-9 (IL-9) and TSLP concentration in the serum of infants with atopic dermatitis. In primary cell cultures, the addition of TSLP led to an increase in IL-9 production from human and mouse Th9 cells, and induced an increase in Signal Transducer and Activator of Transcription 5 (STAT5) activation and binding to the Il9 promoter. In vivo, use of an adoptive transfer model demonstrated that TSLP promoted IL-9-dependent, Th9 cell-induced allergic inflammation by acting directly on T cells. Moreover, transgenic expression of TSLP in the lung stimulated IL-9 production in vivo, and anti-IL-9 treatment attenuated TSLP-induced airway inflammation. Together, our results demonstrate that TSLP promotes Th9 cell differentiation and function, and define a requirement for IL-9 in TSLP-induced allergic inflammation.

Background IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, NKT cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined. Objective To elucidate the role of Th9 cells in promoting mast cell accumulation in models of allergic lung inflammation. Methods Adoptive transfer of OVA-specific Th2 and Th9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation. Results Adoptive transfer experiments demonstrated that recipients of Th9 cells had significantly higher mast cell accumulation and expression of mast cell proteases as compared to control or Th2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4+ T cells, but not NKT cells or innate lymphoid cells, suggesting a T helper cell-dependent phenotype. Rag1−/− mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable to accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment. Conclusion Th9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation.

Although inoculation of COVID-19 vaccines has rolled out globally, there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries. Here, we report on the development of a highly efficacious mRNA vaccine, SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core–shell structured lipopolyplex (LPP) nanoparticles. SW0123 is easy to produce using a large-scale microfluidics-based apparatus. The unique core–shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability, and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration. Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123, represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2, but also a panel of variants including D614G and N501Y variants. In addition, SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge. Taken together, SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.

Background-Bacterial infection with Staphylococcus aureus is a known trigger for worsening of atopic dermatitis (AD); the exact mechanisms by which bacterial infection worsens dermatitis are unknown.