Advisory Committee Chair
Casey T Weaver
Advisory Committee Members
Tika Benveniste
David D Chaplin
Charles O Elson III
Christopher A Klug
Document Type
Dissertation
Date of Award
2009
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
CD4 T cells are a principal component of the adaptive immune system that is required for the efficient elimination of foreign antigens, but dysregulated CD4 T cells responses may result in autoimmune and chronic inflammatory diseases. The differentiation of effector CD4 T cells is directed by cytokines elicited by pathogendriven innate immune responses. Therefore the coordinated innate and adaptive immune responses provide an efficient system for host protection. Our understanding of distinct differentiated CD4 T cells has recently expanded with the discovery of the Th17 lineage, a new subset of effector CD4 T cells that has been implicated in chronic immune responses, host defense and autoimmunity. Th17 cells are characterized by expression of the unique cytokines, IL-17A and IL-17F, and the representative transcription factors, ROR!t and ROR", which are required for their differentiation in response to TGF-# and IL-6. Despite distinct developmental signals, Th17 cells were originally proposed to be a branch of Th1 lineage because there are interesting overlaps between the two lineages. Developing Th17 cells upregulate an inducible receptor IL-23R that binds IL-23, whereas developing Th1 cells induce IL-12R#2 expression that binds to IL-12. Both inducible receptors pair with the constitutively expressed IL-12R#1 chain and drive late events downstream of early Th17 or Th1 lineage commitment. Mice deficient for other Th1 lineage factor (IFN!-/-, IFN!R-/-, IL-12R#2-/-, IL-12p35-/- or STAT1-/-) are susceptible to autoimmunity, whereas deficiency of STAT4 and T-bet can preclude disease, suggesting iii that STAT4 and T-bet have important roles in both Th1 and Th17 responses. In addition, the frequent observation of co-existence of IFN! and IL-17 producing cells in several disease models suggest that a close relationship between Th1 and Th17 lineage. We have developed IL-17F reporter mice that allows us to identify cells expressing this Th17-specific cytokine. Using this model, we found that there is late developmental plasticity of the Th17 lineage, such that IFN! producing cells emerged from Th17 cells following lineage commitment. This transition occurred in a STAT4 and T-bet dependent manner. We also examined the potential consequence of this shift for immunopathology. In a parallel with Th1, we observed that IL-23 acts synergistically with IL-1 or IL-18 to induce unique cytokines of the Th17 lineage in Th17 cells, independently of T cell receptor (TCR) stimulation. Moreover, Th17 cells respond to IL- 18 plus IL-12 to induce IFN! expression that supports late Th17 developmental plasticity. Our results suggest that Th17 effector development is programmed for late developmental plasticity and that non-antigen-specific responses may enhance the role of Th17 cells in autoimmunity and host protection.
Recommended Citation
Lee, Yun Kyung, "Late Development Plasticity in the T Helper 17 Lineage" (2009). All ETDs from UAB. 227.
https://digitalcommons.library.uab.edu/etd-collection/227
