The importance of T cells in the pathogenesis of asthma and other allergic diseases is undisputed. The extent of the T cell response is tightly controlled by a variety of homeostatic mechanisms. T regulatory cells (Tregs) represent a major homeostatic mechanism. Tregs are capable of reversing allergic inflammation in animal models. The number of Tregs in human allergic diseases including asthma has been reported to be low or normal. In preliminary studies we observed that T cells from asthmatic patients are resistant to Treg-mediated suppression. Asthmatic T cells manifest increased proliferative capacity and prolonged survival, which was associated with heightened activation of ERK1/2 and JNK signaling pathways. Inhibition of ERK1/2 but not JNK makes asthmatic T cells susceptible to Tregs. Based upon these preliminary results we hypothesize that T cell resistance against Treg-mediated suppression plays an important role in sustaining the Th2-type inflammation in chronic asthma, and that ERK1/2 and its downstream effector JunB contributes to this resistance. We will test this hypothesis in 2 specific aims-1). Define and characterize T cell resistance against regulatory T cell-mediated inhibition in asthma. 2). Investigate the role of the ERK1/2 signaling pathway in mediating T cell resistance.
Under specific aim #1 we will examine T cell resistance in allergic asthmatic patients, and healthy and disease controls, establish its clinical correlation and disease relevance. We will also examine the role of cytokines and co-stimulatory molecules in establishing T cell resistance.
Under specific aim #2 we will examine whether the ERK1/2 signaling module establishes a self-sustaining mechanism through the induction of a MEK1-dependent positive feedback loop and inhibition of a MKP3-dependent negative feedback loop. We will study the relevance of ERK1/2 and JunB for T cell resistance in human asthma and in a mouse model of chronic asthma using inducible gene knockout and transgenic approaches. The proposal is important because it addresses the mechanism of persistence of chronic inflammation in asthma. T cell resistance against Treg-mediated suppression is a relatively novel observation and is likely to be important for persistent inflammation in chronic diseases beyond asthma. A molecular understanding of T cell resistance could help develop novel therapeutic modalities for treatment of asthma and other allergic diseases.
Asthma is a major public health problem. The mechanism of development of this disease is poorly understood. As a result, disease control is difficult to achieve. One of the important features of asthma is chronic inflammation. This research proposal will examine the mechanism of persistence of this inflammation in asthma. An understanding of chronic inflammation may help develop novel therapeutic modalities for asthma.
