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Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition. Plasmacytoid dendritic cells (pDC) are the major IFN-I-producing cells, but this production returns to baseline soon after viral infection. Here the authors show that this decrease in IFN-I production and related pDC functions may be attributed to suppressed oxidative and glycolytic metabolism of pDCs, with lactate dehydrogenase B identified as a regulator.

Several unique waves of ?? T cells are generated solely in the fetal/neonatal thymus, whereas additional ?? T cell subsets are generated in adults. One intriguing feature of ?? T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived ?? thymocytes in mice. In the Rag2pGFP model, immature (CD24+) ?? thymocytes expressed high levels of GFP whereas only a minority of mature (CD24-) ?? thymocytes were GFP+ Similarly, most peripheral GFP+ ?? T cells were immature. Analysis of ?? recent thymic emigrants (RTEs) indicated that most ?? T cell RTEs were CD24+ and GFP+, and adoptive transfer experiments demonstrated that immature ?? thymocytes can mature outside the thymus. Mature ?? T cells largely did not recirculate to the thymus from the periphery; rather, a population of mature ?? thymocytes that produced IFN-? or IL-17 remained resident in the thymus for at least 60 d. These data support the existence of two populations of ?? T cell RTEs in adult mice: a majority subset that is immature and matures in the periphery after thymic emigration, and a minority subset that completes maturation within the thymus prior to emigration. Additionally, we identified a heterogeneous population of resident ?? thymocytes of unknown functional importance. Collectively, these data shed light on the generation of the ?? T cell compartment in adult mice.

Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.