Innate type-2 effector cell differentiation
To understand how innate Th2-type effector cells acquire the capacity to produce Th2 cytokines, we used IL-4 reporter mice and uncovered that a subset of progenitors possess the capacity to express IL-4, IL-6 and IL-13. These progenitors mostly give rise to basophils and mast cells and retain a limited capacity to generate neutrophils. We showed that a signaling molecule STAT5 was essential in differentiation of the novel progenitors. We found that upregulation of C/EBP alpha, a transcription factor, in the novel progenitors was STAT5-dependent. Induced deletion of C/EBP alpha resulted in reexpression of mast cell-specific genes and also lead to loss of basophil-specific gene expression, indicating that C/EBP alpha is imperative in maintaining basophil-specific genetic programming, including directly transcribing the Il4 gene (Qi, JBC, 2010). We have also made significant progress in understanding molecular controls that direct the novel progenitors toward mast cell lineage.
Strikingly, we demonstrated that the novel progenitors expanded greater than 10-fold when mice were infected with the parasite schistosoma mansoni. Currently, we are focusing on mechanisms by which parasitic infection cause expansion of the novel progenitors (manuscript in preparation).