Signals required for the execution of Th2 effector function

Lazarski, Christopher

Abstract

Signals initiated via ligation of the T cell receptor, co-stimulatory molecules, and cytokine receptors are integrated during an adaptive response to stimulate the differentiation of naive Th cells into either Th1 or Th2 cells. Once activated, newly differentiated T cells transit to the site of infection for subsequent effector function. Little is known about the signals required for effector cells to execute their function but recent data suggests this event is tightly regulated. The resulting cytokine milieu produced by these differentiated T- helper cells eliminates pathogens but can also cause collateral damage. Thus, proper regulation of T cell effector function is necessary to avoid inappropriate or excessive T-helper responses, such as asthma. Our goal is to understand the mechanism within Th2 cells that stimulates the upregulation and release of the IL-4 cytokine. IL-4 is critical for differentiation of Th2 cells and also mediates Th2 function by the activation and recruitment of B cells, mast cells, and eosinophils. The Tec-family kinase Itk is important for both calcium mobilization within T cells and rearrangement of the actin cytoskeleton. Most striking is the necessity of Itk activity within Th2 cells for the upregulation of IL-4 production during secondary stimulation. This feature of Itk represents a unique dependence on Itk for the execution of Th2 effector function. However, it remains unclear how Itk mediates this activity. Our hypothesis is that Itk activity is critical for either stabilizing the transcription factors necessary for IL-4 production, or for opening of the II4 locus itself. Without Itk, Th2 cells produce limited quantities of IL-4 and cannot cure Th2-dependent pathogens while showing a corresponding resistance to asthma induction. We will investigate the accessibility of the II4 locus within WT and Itk -/- Th2 cells during restimulation, and determine the necessity of Th2-specific transcription factor activity for IL-4 production and II4 locus accessibility. Finally, we will investigate the accessibility of the II4 locus within Th2 cells as they develop in vivo. We predict inhibiting Itk activity during an acute response to infection will abrogate ongoing Th2 responses and limit IL-4 production, highlighting an effective therapy to inhibit release of Th2 cytokines. In lay terms, we are investigating how T-helper cells unwind their DNA to facilitate production of proteins called cytokines that are critical for their function. The symptoms of allergy are thought to arise from production of a cytokine termed IL-4. We have demonstrated the protein Itk within T-helper cells is essential for increased production of IL-4. We will investigate how Itk influences IL-4 production, and whether blocking Itk's activity can stop T-helper cells from making IL-4 during an immune response. ? ? ?