Collaborative Gene Regulation in TH9 Cells See article p. 537

Inflamm-aging and Chronic Myelomonocytic Leukemia See article p. 580

Pre-Existing Viral Ab Impacts Heterosubtypic T Cell Priming See article p. 628

One of several E26 transformation-specific (Ets) related transcription factors, ERG, is preferentially expressed in TH9 cells, but its function in IL-9–mediated allergic asthma was unknown. In this Top Read, Kharwadkar et al. (p. 537) showed that ERG promotes IL-9 production in CD4+ T cells and acts cooperatively with two other Ets transcription factors, PU.1 and ETV5, to do so. In vitro, ERG binding at Il9 enhancer regions during early stages of TH9 differentiation supports accumulation of the histone acetyl transferase p300 and is required for PU.1 binding. Deletion of Erg in CD4+ T cells decreased lung IL-producing T cells in a murine model of chronic allergy airway disease, which was exacerbated in the absence of PU.1 and ETV5. Only the combined deficiency of all three Ets transcription factors significantly reduced pulmonary inflammation. Altogether, the data demonstrate the role of ERG as a fail-safe in the development and function of TH9 cells and implicate a more collaborative regulatory network for IL-9 production than had been previously appreciated.

In this Top Read, Ng et al. (p. 628) demonstrate that high levels of pre-existing influenza A virus (IAV)-specific Abs can be detrimental to T cell priming in a subsequent heterosubtypic IAV infection. Mice were treated with low, moderate, and high levels of convalescent plasma harvested from a sublethal infection with IAV, followed by a lethal heterosubtypic IAV infection. Low and moderate IAV-specific Abs were protective against lethal heterosubtypic challenge. However, mice treated with high levels of IAV-specific Abs were undisguisable from unprimed mice, experiencing severe weight loss, high viral burdens, and increased numbers of NK cells, neutrophils, and macrophages in their lungs. The number and functionality of CD4 and CD8 T cells in the lungs of mice treated with high IAV-specific Ab were significantly lower than in the unprimed mice. Interestingly, maternally transferred IAV-specific Abs also interfered with T cell priming in juvenile offspring challenged with a heterosubtypic IAV. Together, these data provide insights into how pre-existing Abs may affect the development of subsequent T cell responses. This is particularly vital information for the development of universal viral vaccines.

In this Top Read, Andina et al. (p. 580) investigated the contributions of the NLRP3 inflammasome and inflamm-aging to chronic myelomonocytic leukemia (CMML) progression. Using peripheral blood from healthy young and old human donors, they found that age drives increased IL-1β production in monocytes following NLRP3 activation. Mechanistically, this phenomenon occurred downstream of TLR1/2 activation in old, but not young human monocytes. In a cohort of CMML patients, individuals could be divided into two groups: high and low IL-1β producers. The high IL-1β producers showed increased NLRP3 activation compared with healthy older controls and displayed increased disease severity and progression. Collectively, this study suggests that inflamm-aging, specifically IL-1β production and NLRP3 activation, may promote CMML disease progression.