IL-4- and IL-13- producing type 2 T cells, are critical for the development of atopy and contribute to asthma pathogenesis by a variety of mechanisms. PGD2, a prostaglandin produced predominantly by mast cells, is involved in chemoattraction of eosinophils and type 2 T cells via the DP2 receptor (CRTH2), a Gi-coupled G protein-coupled receptor (GPCR). However, PGD2 also activates the DP1 receptor, which is a GS-coupled GPCR capable of activating PKA and potentially antagonizing the signaling and effects of the CRTH2 receptor. Both type 2 and non-type 2 T cells express DP1 receptors. How the interplay of the two PGD2 receptors (CRTH2 and DP1) affects type 2 T cell functions, including chemoattraction and IL-13+ T cell accumulation, is unclear. We hypothesize that: 1) PGD2 increases mitogen-stimulated accumulation of IL-13-producing T cells through activation of CRTH2 receptor, but this effect is constrained by concomitant activation of the DP1 receptor;and 2) T cells from asthmatic subjects exhibit, on average, a more dominant CRTH2 (vs. DP1 receptor) receptor response that translates into greater accumulation and chemoattraction of IL-13-producing T cells in response to PGD2. To test this hypothesis, we will characterize the receptor-specific effects of PGD2 on type 2 T cell functions in peripheral blood lymphocytes from atopic asthmatic and nonasthmatic (control) subjects. Functions to be tested include: 1) activation/inhibition of PKA;2) activation/inhibition of MAPK's and Akt;3) antigen -independent and -dependent accumulation of type 2 T cells;and 3) chemoattraction of type 2 T cells. This proposal provides a novel approach for examining the contribution of PGD2 receptors in asthma: 1) comparisons between asthmatic and nonasthmatic populations for the effects of PGD2 on cellular functions have not been previously reported;and 2) the interplay between the two PGD2 receptors on mitogen-stimulated accumulation type 2 T cells, and the signaling mechanisms involved, have not been previously explored. Knowledge of the competitive balance between the "good" and "bad" effects of PGD2 is critical for determining a feasible therapeutic strategy targeting PGD2 receptor subtypes in the treatment of asthma, as well as other inflammatory diseases. PUBLIC HEALTH RELEVANCE. PGD2 is an important inflammatory mediator found in the lungs of asthmatics after exposure to allergen. In this study, we will examine how this molecule affects how immune cells increase in number when exposed to PGD2, and if asthmatics are more sensitive to the "bad" effects of PGD2. Results will help us understand how PGD2 drives allergic inflammation occurs, and may suggest ways to pharmacologically balance the "good" and "bad" effects of PGD2.

R21AI076699

2009-05-22

2011-04-30