ROLE OF NF-κB-ASSOCIATED FACTORS IN T CELL DEVELOPMENT AND FUNCTION

Open Access
Author:
Lee, Joon Hyung
Graduate Program:
Cell and Molecular Biology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
July 17, 2009
Committee Members:
  • Christopher Charles Norbury, Dissertation Advisor
  • Shao Cong Sun, Committee Chair
  • Christopher Charles Norbury, Committee Chair
  • Robert Harold Bonneau, Committee Member
  • Edward Joseph Gunther, Committee Member
  • Barbara Miller, Committee Member
Keywords:
  • CYLD
  • NFkappaB
  • NKT
  • Treg
Abstract:
The immune system is a defensive mechanism that protects an organism from disease by identifying and neutralizing invading pathogens. The proper functioning of the mammalian immune system requires participation and cooperation of different immune cell types, with the ability to distinguish self from non-self. Despite its protective functions, the immune system can also be a double-edged sword, as aberrant activation of the immune system can cause chronic inflammation and autoimmune diseases. Therefore, it is important to understand the mechanism by which immune responses are generated and regulated. Various intracellular signal transduction pathways and transcription factors are involved in the activation and regulation of immune responses. NF-κB is a key transcription factor in the immune system that regulates the development, function, homeostasis, and survival of various immune cells. NF-κB activation typically occurs after a stimulatory signal received at the cell surface is relayed to NF-κB through complex intracellular signaling pathways. Therefore, the outcome of NF-κB activation is critically determined by the function of molecules involved in the NF-κB signaling pathways. This thesis addresses the role of NF-κB-associated molecules in the development, differentiation, and function of T cells. Our studies show that CYLD, a negative regulator of NF-κB activation, is critical for development of natural killer T (NKT) cells. In addition, Carma1, a key molecule involved in the T cell receptor-mediated NF-κB activation, is required for the development of suppressive regulatory T cells (Tregs). Lastly, p105, a NF-κB precursor molecule with NF-κB inhibitor function, plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. The major findings are summarized below. 1. CYLD regulates IL-7 signaling and ICOS expression in the development of natural killer T cells. Natural killer T (NKT) cells modulate immune responses against pathogens and tumors. Utilizing CYLD-deficient mice, we show that CYLD, a deubiquitylase that negatively regulates NFκB activation, plays a critical role in NKT cell development. Unlike most of the known regulators of NKT cell development, CYLD is dispensable for NKT cell maturation but is required for the survival of immature NKT cells. The survival defect of immature NKT cells was associated with decreased expression of ICOS, a costimulatory molecule required for the survival and homeostasis of NKT cells, and signaling attenuation of an NKT-survival cytokine, IL-7. CYLD positively regulate ICOS expression and IL-7 signaling by preventing hyper-activation of NF-κB in immature NKT cells. Thus, CYLD regulates NKT cell development through a mechanism involving modulation of IL-7 signaling and ICOS expression. 2. Carma1 regulates development of regulatory T cells in the thymus. Regulatory T cells (Tregs) play a critical role in the preservation of self-tolerance and prevention of autoimmunity. We show that Carma1, a signaling molecule involved in the T cell receptor (TCR)-mediated NF-κB activation, is essential for development of Tregs in the thymus. Carma1 deficiency leads to attenuation of IL-2 signaling, a cytokine that is critical for the development of Tregs in the thymus. This IL-2 signaling defect in Carma1-knockout mice is associated with low expression of IL-2 receptor β subunit (IL-2Rβ). Thus, Carma1 regulates thymic Treg development through modulation of IL-2 signaling via the IL-2Rβ. 3. NF-kappa B1 p105 regulates T cell homeostasis and prevents chronic inflammation. NF-κB transcription factors are regulated by a family of inhibitors called IκBs. NF-κB1 precursor, p105, contains IκB-like domain in their C-terminal and can function as NF-κB inhibitors. In this study, we show that p105 plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. Mice that express mature NF-κB1, p50, in the absence of p105, spontaneously develop T cell-mediated intestinal inflammation. Consistent with the inflammatory phenotype, p105-deficient mice have increased frequency of memory/effector T cells in the peripheral lymphoid organs. Additionally, p105 deficiency renders CD4+ T cells more resistant to Treg-mediated suppression, while promoting differentiation of inflammatory Th17 CD4+ helper cells. Therefore, p105 plays critical roles in the regulation of T cell homeostasis and differentiation and the control of chronic inflammation.