No problem inhaling?

  • Published 2004 in Nature Reviews Immunology

Abstract

According to new research published in Immunity, calcineurin is required for positive but not negative selection of developing T cells in the thymus. Before T cells emigrate from the thymus, they undergo a selection process, which occurs at the CD4 CD8 double-positive (DP) stage of thymocyte development (before the downregulation of either CD4 or CD8 expression). It is thought that only those T cells able to engage in transient interactions with self-MHC molecules are maintained (positive selection) and that those T cells displaying strong reactivity are eliminated (negative selection). But what is the mechanism by which low-intensity interactions result in cell survival and proliferation and high-intensity interactions result in cell death? Neilson and colleagues set out to explore this by examining the role of calcineurin (which activates Nfatc subunits) in thymic selection. The authors generated mice with a targeted deletion of the regulatory subunit of calcineurin (Cnb1), rendering all isoforms of calcineurin inactive in thymocytes but not non-lymphoid components of the thymus. The thymi of these mice were found to have essentially no single-positive (SP) T cells. This complete failure to progress from the DP to the SP stage indicates that calcineurin is required for positive selection. DP thymocytes were also unable to upregulate the expression of cell-surface markers associated with positive selection, such as the β-chain of the T-cell receptor (TCR-β), CD69 and CD5. Furthermore, positive selection of cells expressing a clonotypic TCR was blocked in the absence of calcineurin. No problem inhaling? Research presented at the recent American Academy of Allergy, Asthma and Immunology (AAAI) annual meeting indicates that a component in asthma inhalers might cancel out the beneficial anti-inflammatory effects of inhaled steroids (AAAI). Albuterol (Salbutamol) is a β-agonist used in asthma inhalers to promote airway dilation. It is composed of equal amounts of two isomers — one active, R-albuterol, and one inactive, S-albuterol. Studies carried out at the University of Pittsburgh by Dr Bill Ameredes indicated that the anti-inflammatory effects of steroids were enhanced by R-albuterol; however, S-albuterol abolished the antiinflammatory steroid effects. Dr Ameredes said, “These results indicate that S-albuterol may diminish the beneficial anti-inflammatory effects of steroids... ” (BBC), and that therefore, we need to consider “the possibility that current combination therapies ... may not be realizing their full potential” (Patient Health International). Despite these results, experts are keen to stress that patients should not stop taking their medication. “These findings are related only to Salbutamol used in combination with inhaled steroids, and if you are using this combination then your asthma should be under control and you shouldn’t actually need to take your reliever medicine very often, if at all,” said Katie Shepard, the National Asthma Campaign’s care development manager (National Asthma Campaign). Furthermore, albuterol is only designed to relieve asthma symptoms in the short-term, and as Martyn Partridge, Chief Medical Advisor to the National Asthma Campaign, said, “If you’re currently using Salbutamol more than three times a week, then you should be on a low-dose inhaled steroid. You’d take that regularly and you’d find that you didn’t need the Salbutamol” (The Guardian). IN THE NEWS

DOI: 10.1038/nri1365

Cite this paper

@article{2004NoPI, title={No problem inhaling?}, author={}, journal={Nature Reviews Immunology}, year={2004}, volume={4}, pages={318-318} }