New Insights into the Generation of CD4 Memory May Shape Future Vaccine Strategies for Influenza

Influenza viral evolution presents a formidable challenge to vaccination due to the virus\u27 ability to rapidly mutate to evade immune responses. Live influenza infections generate large and diverse CD4 effector T cell responses that yield highly protective, long-lasting CD4 T cell memory that can target conserved viral epitopes. We review advances in our understanding of mechanisms involved in generating CD4 T cell responses against the influenza A virus (IAV), focusing on specialized follicular helper (TFH) and CD4 cytotoxic (ThCTL) effector subsets and on CD4 T cell memory. We also discuss two recent findings in context of enhancing vaccine responses. First, helper T cells require priming with APC secreting high levels of IL-6. Second, the transition of IAV-generated effectors to memory depends on IL-2, costimulation and antigen signals, just before effectors reach peak numbers, defined as the memory checkpoint. The need for these signals during the checkpoint could explain why many current influenza vaccines are poorly effective and elicit poor cellular immunity. We suggest that CD4 memory generation can be enhanced by re-vaccinating at this time. Our best hope lies in a universal vaccine that will not need to be formulated yearly against seasonal antigenically novel influenza strains and will also be protective against a pandemic strain. We suggest a vaccine approach that elicits a powerful T cell response, by initially inducing high levels of APC activation and later providing antigen at the memory checkpoint, may take us a step closer to such a universal influenza vaccine

Rapid default transition of CD4 T cell effectors to functional memory cells

The majority of highly activated CD4 T cell effectors die after antigen clearance, but a small number revert to a resting state, becoming memory cells with unique functional attributes. It is currently unclear when after antigen clearance effectors return to rest and acquire important memory properties. We follow well-defined cohorts of CD4 T cells through the effector-to-memory transition by analyzing phenotype, important functional properties, and gene expression profiles. We find that the transition from effector to memory is rapid in that effectors rested for only 3 d closely resemble canonical memory cells rested for 60 d or longer in the absence of antigen. This is true for both Th1 and Th2 lineages, and occurs whether CD4 T cell effectors rest in vivo or in vitro, suggesting a default pathway. We find that the effector–memory transition at the level of gene expression occurs in two stages: a rapid loss of expression of a myriad of effector-associated genes, and a more gradual gain of expression of a cohort of genes uniquely associated with memory cells rested for extended periods

Toward Large-Area Sub-Arcsecond X-Ray Telescopes II

In order to advance significantly scientific objectives, future x-ray astronomy missions will likely call for x-ray telescopes with large aperture areas (approx. = 3 sq m) and fine angular resolution (approx. = 1"). Achieving such performance is programmatically and technologically challenging due to the mass and envelope constraints of space-borne telescopes and to the need for densely nested grazing-incidence optics. Such an x-ray telescope will require precision fabrication, alignment, mounting, and assembly of large areas (approx. = 600 sq m) of lightweight (approx. = 2 kg/sq m areal density) high-quality mirrors, at an acceptable cost (approx. = 1 M$/sq m of mirror surface area). This paper reviews relevant programmatic and technological issues, as well as possible approaches for addressing these issues-including direct fabrication of monocrystalline silicon mirrors, active (in-space adjustable) figure correction of replicated mirrors, static post-fabrication correction using ion implantation, differential erosion or deposition, and coating-stress manipulation of thin substrates

Lynx Mission Concept Status

Lynx is a concept under study for prioritization in the 2020 Astrophysics Decadal Survey. Providing orders of magnitude increase in sensitivity over Chandra, Lynx will examine the first black holes and their galaxies, map the large-scale structure and galactic halos, and shed new light on the environments of young stars and their planetary systems. In order to meet the Lynx science goals, the telescope consists of a high-angular resolution optical assembly complemented by an instrument suite that may include a High Definition X-ray Imager, X-ray Microcalorimeter and an X-ray Grating Spectrometer. The telescope is integrated onto the spacecraft to form a comprehensive observatory concept. Progress on the formulation of the Lynx telescope and observatory configuration is reported in this paper

Toward Large-Area Sub-Arcsecond X-Ray Telescopes

The future of x-ray astronomy depends upon development of x-ray telescopes with larger aperture areas (>1 sq m) and finer angular resolution(100 sq m) of lightweight (1 kg/sq m areal density) high quality mirrors-possibly entailing active (in-space adjustable) alignment and figure correction. This paper discusses relevant programmatic and technological issues and summarizes progress toward large area sub-arcsecond x-ray telescopes. Key words: X-ray telescopes, x-ray optics, active optics, electroactive devices, silicon mirrors, differential deposition, ion implantation

Regulation of CD4 T Cell Responses by the Transcription Factor Eomesodermin

Central to the impacts of CD4 T cells, both positive in settings of infectious disease and cancer and negative in the settings of autoimmunity and allergy, is their ability to differentiate into distinct effector subsets with specialized functions. The programming required to support such responses is largely dictated by lineage-specifying transcription factors, often called ‘master regulators’. However, it is increasingly clear that many aspects of CD4 T cell immunobiology that can determine the outcomes of disease states involve a broader transcriptional network. Eomesodermin (Eomes) is emerging as an important member of this class of transcription factors. While best studied in CD8 T cells and NK cells, an increasing body of work has focused on impacts of Eomes expression in CD4 T cell responses in an array of different settings. Here, we focus on the varied impacts reported in these studies that, together, indicate the potential of targeting Eomes expression in CD4 T cells as a strategy to improve a variety of clinical outcomes