Investigation Into Regulatory Mechanisms That Limit The Th2 Response in a Mouse Model of Allergic Asthma

The prevalence of asthma has markedly increased in recent decades. Asthma affects approximately ten percent of the population of the United States, and is the leading cause of childhood hospitalization. This epidemic has been attributed to air pollution, childhood immunizations and a more sanitary living environment. Allergic asthma is clinically characterized by airway hyperreactivity (AHR), increased mucus production and airway remodeling. On the cellular level, pulmonary eosinophilic infiltration and augmented levels of serum IgE arise as a consequence of a CD4+ Th2 cell response in the airway following exposure to allergen. It has been proposed that the chronic inflammation and associated airway events evident in this disease stem from a failure to regulate the underlying immune response. How these events are regulated in the healthy lung is yet unclear. In studies to investigate the mechanisms underlying such regulation we found that firstly, co-transfer of expanded natural CD4+ CD25+ Foxp3+ regulatory T cells (nTregs) mediated regulation of CD4+ Th17 effector cells as exemplified by diminished levels of IL-17 and decreased neutrophilic infiltration in the airways. In contrast, co-transfer of nTregs did not attenuate the lung inflammation elicited by CD4+ Th2 or Th1 polarized cells. Interestingly, using the C129.IL4GFP mice we found that nTregs have the capacity to inhibit IL-4 production and Th2 differentiation in vitro. Secondly, mice with genetically disrupted receptors (IP-/-) for the lipid-mediator prostacyclin (PGI2), demonstrated increased airway inflammation, eosinophilic infiltration and airway hyperreactivity following immunization and repeated aerosol challenge with ovalbumin. Moreover these mice displayed reduced serum immunoglobulin levels. In summary, nTregs serve a specific function in controlling Th17 cell effector functions, but not Th1 or Th2 inflammation. Additionally, PGI2-IP signaling is an important pathway for inhibiting allergic pulmonary inflammation by controlling CD4+ Th2 cell effector functions