Checkpoints in the regulation of T helper 1 responses

Abstract

We have described the work of our own and others characterizing some of the mechanisms of Th1 and Th2 development (Fig. 5). IL-12 is a key cytokine in driving Th1 cell development, and in certain mouse strains such as the BALB/c mouse, IL-1α and IL-18 act as cofactors in this process. IL-1α and IL-18, although belonging to the IL-1 family of cytokines, have very different actions on differentiated Th1 and Th2 cells. IL-1α can induce proliferation of Th2 cells, while IL-18 synergizes with IL-12 to induce maximal IFN-γ production by Th1 cells. IL-1α and IL-18 bind to distinct and differentially regulated receptors on Th2 versus Th1 cells, respectively, and induce IRAK phosphorylation and NFκB nuclear translocation. Dissection of the molecular mechanisms of Th1 and Th2 development led to the observations that ectopic expression of IL-12Rβ2 in Th2 cells, although it resulted in the restoration of IL-12 signaling and proliferation, did not allow IL-12 induced IFN-γ production nor downregulation of IL-4 production. The expression and activation of a conditionally active form of STAT6 in developing Th1 cells resulted in reduced IFN-γ and enhanced IL-4 production; however, the phenotype of committed Th1 cells could not be altered. In contrast ectopic expression of the Th2-specific transcription factor GATA-3 was able to upregulate IL-4 and IL-5 in both developing and committed Th1 cells, suggesting that this transcription factor may play a key role in Th2 development.