Top Reads

In this Top Read, Weizman et al. (p. 1146) demonstrate that conventional type 2 dendritic cells (DC2) in lungs direct IFN-γ production by local NK cells to limit metastasis. Targeted ablation of lung resident DC2s, but not peripheral DCs, resulted in increased metastatic burden. IL-12p40 produced by DC2s was necessary for control of the tumor. Systematic deletion of individual cell types revealed that innate lymphoid cells (ILCs) were vital for preventing metastatic burden. Of the ILCs tested, only NK cells produced significant IFN-γ in lung tumor models. Depletion of either NK cells or IFN-γ resulted in similar increases in tumor burden. DC-specific deletion of IRF3 and IRF7 both increased metastatic burden and decreased IFN-γ production, suggesting that these transcription factors were necessary to control early tumor immunity. Finally, confocal microscopy showed early colocalization of NK cells and DC2s near metastatic cells in the lung. Together, these data demonstrate a new DC2-NK cell axis that is necessary to limit early tumor burden.

In this Top Read, Kurihara et al. (p. 1086) reported that intranasal infection with Chlamydia pneumoniae induces lipolysis and pathology in infected lung white adipose tissue (WAT), which is dependent on expression of fatty acid–binding protein 4 (FABP4). Although both control and FABP4^−/− mice became infected with C. pneumoniae, FABP4 deficiency protected mice from excessive chlamydial growth in WAT, as well as several features of metabolic dysfunction and inflammation. These included reduced adipocyte size, activation of hormone-sensitive lipase (HSL), increased local and systemic inflammatory cytokines (e.g., TNFα and IL-6), polarization of inflammatory M1-like adipose tissue macrophages in WAT, and reduced body weight. Mechanistically, increased activation of HSL in infected WAT cultures of control, but not FABP4^−/−, mice correlated with elevated expression of endoplasmic reticulum (ER) stress-marker proteins, suggesting that ER stress promotes WAT lipolysis in a FABP4-dependent manner. Chemical inhibition of ER stress in infected control mice reversed adipocyte pathology, low body weight, as well as glucose intolerance and insulin resistance. Altogether, the data show that FABP4 and ER stress link pulmonary C. pneumoniae infection with systemic inflammation and provide potential therapeutic targets for some infection-induced metabolic disorders.

In this Top Read, Fitzpatrick et al. (p. 1156) developed a bead-based assay to assess the quality of peptide:MHC tetramers. The need for better tetramer quality control was demonstrated using multiple batches produced using the same protocols. On the day of production, the tetramer batches had similar binding, though storage conditions and batch variability affected binding over time. Using compensation beads bound to a mAb specific for either the tetramer peptide or the fluorophore, as a control, the authors detected batch-related differences in tetramer binding. The assay was expanded to include multiple Abs for the tetramer peptide, each with a different fluorophore. Excess free peptide from the tetramer preparations inhibited high affinity Ab binding, demonstrating the assay could be used to detect production errors resulting in under-loaded tetramer. Finally, Abs to various parts of the tetramer were used to indicate a decline in tetramer integrity over time. Together, these data provide validation of a bead-based assay, which can rapidly and robustly provide quality control for peptide:MHC tetramers, thereby reducing experimental variability.