Regulation of T cells in airway disease by beta-agonist

Abstract

It is widely recognized that Th2 cytokines derived from T cells play a major role in the development of allergic lung inflammation that causes most asthma. Beta-agonists are important rescue and maintenance therapies for asthma, yet our understanding of beta-agonist effects on T cell biology is surprisingly poor. Recent studies using both cell culture and more integrative models are beginning to reveal beta-agonist regulation of T cell signaling and function that may be important in the pathogenesis and treatment of asthma and possibly other inflammatory diseases. Here we provide a comprehensive review of the literature concerning beta-agonist effects on T cells, and discuss the relevance of emerging paradigms of beta-adrenergic receptor signaling to T cell function.

Figure 1

Proximal TCR signaling and regulation by Gs-coupled receptors and PKA. Engagement of TCR with cognate peptide antigen presented by MHC molecules promotes the membrane recruitment and activation of the Src kinases Lck and Fyn (Fyn not shown), phosphorylation of immunoreceptor tyrosine-based activation motifs within the CD3 complex, and ultimate recruitment and activation of ZAP-70. Active ZAP-70 then leads to activation of multiple downstream signaling cascades via activation of LAT and SLP-76 (as depicted in Figure 2). Agonist-activated Gs-coupled receptors such as the Beta₂AR promote adenylyl cyclase activity resulting in hydrolysis of ATP into cAMP. cAMP binds the regulatory subunits of the cAMP-dependent protein kinase (PKA, shown docking on an AKAP) which induce release and activation of PKA catalytic subunits. The Src kinase Csk phosphorylates Lck and inhibits its activity. Csk resides in lipids rafts in association with Cbp/PAG in resting T cells, but is transiently displaced to the cytosol upon T cell activation. PKA phosphorylates Csk on Ser 364 to increase Csk activity, which results in Lck inhibition, and inhibition of TCR zeta–chain phosphorylation, and proximal TCR signaling.

Figure 2

Downstream T-cell signaling events and impact of PKA. Major downstream signaling cascades resulting from MHC:cognate peptide stimulation of TCR:CD3 complex are depicted. Critical signaling molecules transmitting upstream signals from ZAP-70 to multiple major effector signaling pathways (e.g., MAPK, NF-kappaB, Ca²⁺/NF-AT pathways) are represented by black shading. Intermediate signaling moieties and adaptors are shaded gray. Terminal effector molecules (or complexes), which are responsible for the activation/nuclear translocation of transcription factors, are shaded yellow. Select transcription factors activated as a result of TCR/CD3-mediated stimulation are shaded blue. Inhibition events are indicated by T. Signaling molecules reported to be inhibited by catalytically active PKA are shaded red. This schematic is intended to present major signaling events in antigen-activated T cells, and may not include all signaling molecules, adaptors, and transcription factors involved in this complex system.

Figure 3

Impact of Th2-derived cytokines on airway inflammation and remodeling.