T helper cell differentiation
CD4+ T helper cells (Th) are of critical importance in health and in diseases. Many types of Th cell-mediated immune responses have been uncovered. Each type of Th responses is carried out by a specialized CD4+ Th subset and by a specialized innate type of effector cells. For example, type-2 immune responses are mounted by Th2 cells as well as Th2 cytokine-producing innate effector cells, such as basophils, eosinophils and mast cells. Type-1 immune responses provide cellular defense against infection with intracellular pathogens, whereas Type-2 immune responses help antibody responses. Type-2 immune responses have also been shown to be the dominant immune response in allergic diseases and allergic asthma. Type-3 and 9 immune response cells exert their biological effects mainly on basophil and mast cell differentiation. Type-17 immune responses are critical in recruiting neutrophils, inducing chemokine production, and causing inflammation and fibrosis. Type-22 immune responses are involved in epidermal immunity and remodeling.
Th1 and Th2 polarization can be achieved through a positive reinforcement of genetic programming that leads to one lineage commitment and through a negative reinforcement that suppresses developmental potential of the other lineage. Knowledge gained from this area of research could help to develop treatment for allergy and asthma and then to devise a vaccine strategy to boost asthmatic patient’s immunity to fight against viral and bacterial infections.
Over the last decade, we have investigated the mechanism by which Th1 promoting factors, such as IFN-y- and IL-27 (a cytokine produced by dentritic cell), suppress the Il4 gene expression. We demonstrated that IFN-y- is essential in maintaining Th1 phenotype in part by inhibiting STAT6 recruitment to the IL-4 Receptor (Zhang, J Exp. Med. 2001; Huang Z, Journal of Immunology, 2005). We further showed that continuous T-bet expression (a Th1 master transcription factor) is required to silence the IL-4-producing potential in Th1 cells (Zhuang, Immunology, 2009). We have mapped signaling pathways that lead to the silencing of the IL-4-producing potential in Th1 cells (Zhuang, Immunology, 2009) and demonstrated that the IL-12-STAT4 pathway and the IFN-y-STAT1 pathway converge at the point of T-bet (Zhuang, Journal of Interferon & Cytokine Research, 2009). Compared with the IL-12-STAT4 pathway, the IFN-y-STAT1-T-bet signaling pathway is the major pathway that leads to silencing of the IL-4-producing potential of Th1 cells (Zhuang, J. Interferon and Cytokine Research, 2009; Huang, H, Frontier Bioscience, 2011). We have studied chromatin modifications that are required to silence the Il4 locus in Th1 cells (unpublished observation).
Interestingly, on the other side of Th1/2 dichotomy, we recently found that Th2-promoting factor inhibit Th1 developmental potential by shutting down the key Th1-promoting signaling pathway; we show that IL-4 inhibits STAT1 and STAT2, but not STAT3 and STAT4, phosphorylation in Th2 cells (manuscript submitted). We have attempted to translate our knowledge gained from investigation of basic Th biology into development of diagnostic method and potential treatment or into greater understanding of allergy and asthma pathogenesis. Currently, we are analyzing novel Th cytokines in elder asthmatic patients and mechanisms by which CD4 T cells from asthmatic patients resist IL-27-mediated inhibition.