Control of infection relies on the adoption of an appropriate effector cell fate characterized by expression of a discrete pattern of cytokine genes. Most defined are the Th1 and Th2 effector fates that are associated with the defense against intracellular and intestinal pathogens respectively. Many disease states, both autoimmune and infectious, result from a robust but inappropriate immune response. Our long-term aim is to understand the molecular and cellular requirements for establishing distinct cytokine programs. Such knowledge will enable an informed approach to promoting the appropriate effector T-cell fate for a given immunologic challenge. How do naive T-cells acquire discrete cytokine profiles. Signals from both the T-cell receptor (TCR) and cytokine receptors are necessary for stable Th1 and Th2 differentiation. Manipulations that appear to specifically target the TCR signal pathway can influence the Thl/Th2 balance. It is unclear how T-cell activation signals might be summated or modulated in the cell to affect cytokine gene expression. Recent data suggest that distinct transcription factors mediate cytokine expression in Th1 (IFNgamma expression) and Th2 (IL-4 expression) cells. The biochemical pathways that link TCR engagement to these transcription factors remain obscure. Our previous work revealed a novel role for the T-cell Tec kinase, Itk, in signals required for Th2 development. Itk-deficient CD4+ T-cells failed to generate effective Th2 responses to a variety of infectious challenges in vivo. Importantly, Itk was dispensable in Th1 development. These findings support the notion that distinct TCR signaling pathways are required for Th1 and Th2 development. Such a scheme predicts that one could abrogate one effector program without compromising the other. Indeed, Itk itself may represent a target for modulating the dysregulated Th2 responses associated with allergy and asthma. Members of the Tec kinase family have been implicated in many stages of lymphocyte differentiation including repertoire selection, cytokine gene expression and growth factor responsiveness. This application investigates Itk's role in Th differentiation from the standpoints of development, regulation of IL-4 expression and the expansion/survival of the Th2 lineage. Our central hypothesis is that Itk conveys information on the quality of TCR/MHC interaction from the cell surface to the nucleus to modulate Th differentiation and survival
