Neonatal hyperoxia promotes asthma-like features through IL-33–dependent ILC2 responses

Background Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. Objective We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. Methods Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. A group of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and TH and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. Results Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. Conclusions These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity

Mechanisms of cooperation between antigenic and cytokine signals in CD8 T cell activation

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Our adaptive immune system is comprised of white-blood cells that distinguish self- (our own) from foreignproteins (DNA products) and are capable of establishing long-lived immunity against harmful microbes and cancer. One of the cellular subsets that mediate cellular immunity, or protection by distinction, called CD8 T cells, specifically kill only virally infected or cancerous cells. In order to do so, CD8 T cells must integrate signals from the environment that include sensing both small pieces of proteins presented by other immune cells and proteins produced by the inflammatory, or "early-warning", anti-microbial immune response. It is not clear how these two signals (antigen and inflammatory proteins) integrate to activate the cell-mediated immune response that leads to direct killing of infected cells. Answers to how these signals cooperate to activate the immune system, could provide insight into new therapies for caner, autoimmune diseases, and vaccinations. Here, we find specific conditions that lead to activation of CD8 T cells potentially able to respond to self-antigens important for auto-immunity and cancer. Specifically we found that the strength of signal through the receptor that recognizes small pieces of protein, influenced the T cell's ability to sense inflammatory proteins. Further, we found that signals from the inflammatory environment utilize the cell-membrane receptor used to sense small pieces of proteins from self or foreign sources. In an unexpected way response to inflammatory proteins required CD8 T cells to recognize, or sense, self-antigens

Low-Affinity T Cells Are Programmed to Maintain Normal Primary Responses but Are Impaired in Their Recall to Low-Affinity Ligands

T cell responses to low-affinity T cell receptor (TCR) ligands occur in the context of infection, tumors, and autoimmunity despite diminished TCR signal strength. The processes that enable such responses remain unclear. We show that distinct mechanisms drive effector/memory development in high- and low-affinity T cells. Low-affinity cells preferentially differentiate into memory precursors of a central memory phenotype that are interleukin (IL)-12Rlo, IL-7Rhi, and Eomeshi. Strikingly, in contrast to naive cells, low-affinity memory cells were impaired in the response to low- but not high-affinity ligands, indicating that low-affinity cells are programmed to generate diverse immune responses while avoiding autoreactivity. Affinity and antigen dose directly correlated with IL-12R signal input and T-bet but not with Eomes expression because low- affinity signals were more potent inducers of Eomes at a high antigen dose. Our studies explain how weak antigenic signals induce complete primary immune responses and provide a framework for therapeutic intervention