Spectrum of T-lymphocyte activities regulating allergic lung inflammation

Abstract

Despite advances in the treatment of asthma, optimization of symptom control remains an unmet need in many patients. These patients, labeled severe asthma, are responsible for a substantial fraction of the disease burden. In these patients, research is needed to define the cellular and molecular pathways contributing to disease which in large part are refractory to corticosteroid treatment. The causes of steroid-resistant asthma are multifactorial and result from complex interactions of genetics, environmental factors, and innate and adaptive immunity. Adaptive immunity, addressed here, integrates the activities of distinct T-cell subsets and by definition is dynamic and responsive to an ever-changing environment and the influences of epigenetic modifications. These T-cell subsets exhibit different susceptibilities to the actions of corticosteroids and, in some, corticosteroids enhance their functional activation. Moreover, these subsets are not fixed in lineage differentiation but can undergo transcriptional reprogramming in a bidirectional manner between protective and pathogenic effector states. Together, these factors contribute to asthma heterogeneity between patients but also in the same patient at different stages of their disease. Only by carefully defining mechanistic pathways, delineating their sensitivity to corticosteroids, and determining the balance between regulatory and effector pathways will precision medicine become a reality with selective and effective application of targeted therapies.

Keywords: T-cell subsets; asthma; plasticity; steroid sensitivity.

Figure 1. Recruitment of CD8⁺ Teff to the lung

Schematic of the CD8⁺/BLT1⁺/IL-13⁺ axis in asthma pathogenesis. Lung mast cells, activated through the high affinity IgE receptor (FcεRI) after cross-linking with allergen, initiate a cascade resulting in the rapid synthesis and release of LTB4. Activated CD8⁺ Teff upregulate expression of BLT1, the high-affinity receptor for LTB4 and binding of LTB4 to BLT1 on CD8⁺ Teff results in their recruitment and accumulation in the lung. In the lung, in the presence of IL-4, CD8⁺ Teff undergo transcriptional reprogramming and differentiate into Tc2 cells releasing IL-13, which affects many of the cell types involved in asthma pathogenesis. PLA2, Phospholipase A2; FLAP, 5-LO activating protein; LTA4H, LTA4 hydrolase.

Figure 2. Pathways signaling the suppressive or enhancing activities of nTregs

nTregs obtained from WT (CD8⁺) donors when transferred into sensitized and challenged WT recipients suppress the development of lung allergic responses. Interactions between CD8 and MHC I are essential. In the absence of CD8 (CD8-deficient mice), nTregs from these mice when transferred into sensitized and challenged WT recipients, enhance development of lung allergic responses. Enhancement is triggered by transcriptional reprogramming of the nTregs, mediated through ligation of GITR and activation of the GITRL-GITR-JNK pathway. In CD8^+/+ mice signaling through CD8-MHC I dominates and is associated with the maintenance of the regulatory phenotype and suppressive activities of nTregs even in face of GITR ligation.