CD4+ helper T (Th) cells play central regulatory roles in immune responses. After activation, these cells differentiate into Th1 or Th2 effector cells, which specialize in producing distinct cytokines to mediate different types of immune responses. Despite recent progress in identifying lineage-specific signal transduction pathways and transcription factors that mediate Th differentiation, how each effector cytokine is independently regulated in the context of various immune responses has not been fully understood. Th activation, differentiation and cytokine production are regulated in part by co-stimulatory receptors. Inducible co-stimulator (ICOS) is a novel member of the CD28 family that is not expressed by naive Th cells but induced after Th activation. In the effector stage, ICOS expression is selectively higher in Th2 than Th1 cells. ICOS ligand, B7H/B7RP-1 although rarely detectable in dendritic cells, is expressed by B cells and induced in non-lymphoid tissues by inflammation. We recently generated and analyzed mice deficient in ICOS. ICOS-/- Th cells had deficits not in the general Th differentiation but rather in expression of specific cytokines such as IL-2 and IL-4 in vitro and in vivo. Consistently in a murine asthma model, ICOS-deficient mice, although exhibited normal IL-5 production and the consequential eosinophil infiltration in the airway, were impaired in IL-4 expression and IL-4-dependent lgE production. Furthermore, ICOS mediates humoral immune responses by regulation of germinal center reactions. Therefore, ICOS provides a unique system for us to study regulation of selective effector cytokine production by Th2 cells. In this grant, we will first study the signaling mechanism of ICOS co-stimulatory receptor. We have recently found that ICOS cytoplasmic domain associates with the p85 regulatory subunit of phosphoinositide 3 (PI-3) kinase, which is dependent on the YMxM motif in ICOS. We will use retroviral transduction and knock-in genetics approaches to address the role of this motif in ICOS-mediated cytokine expression. Secondly, we will identify the defects of cytokine gene transcription in ICOS-/- Th cells. We will study how ICOS regulates IL-4 expression and determine if transcription factors acting on lL-4 proximal promoter are defective in ICOS-/- Th cells. These studies will greatly advance our knowledge in the novel immunoregulatory pathway mediated by ICOS, may help rationalize future design of immunotherapy against asthma.
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