application) CD4+ T lymphocytes are the predominant regulatory cells of the immune system and exert their effects through the expression of specific cell surface molecules and the secretion of cytokines. Following exposure to antigen, naive CD4+ T cells begin a complex process of differentiation and have several potential cell fates. The functional outcome of this response is observed clinically as T cell mediated immunity, autoimmune disease, transplant rejection or immune tolerance depending on the multiple interactions between the lymphocytes and their environment. Understanding the molecular mechanisms that govern T cell fate decisions during the peripheral immune response is critical to developing treatment strategies for a variety of diseases. T lymphocyte differentiation begins when the T cell physically interacts with an antigen presenting cell (APC) and receives signals through its antigen specific T cell receptor and associated cell surface molecules. Depending upon the quality of this initial stimulus, different T cell populations are observed (anergic, apoptotic, effector, and memory), i.e. multiple fates. Experimental conditions that favor the generation of these particular cell fates have been identified and some of the molecular mechanisms have been elucidated. Another mechanism that is known to regulate cell fate determination is that of the Notch receptor signaling pathway. Engagement of Notch by one of its ligands activates a pathway, which has the potential to regulate the transcription of multiple genes and gene families involved in cell differentiation. Experimental evidence in thymocyte ontogeny has demonstrated that the Notch signaling pathway has a profound effect on differentiation (CD4 vs. CDS lineage commitment), proliferation (delaying cell cycle kinetics) and death (anti-apoptotic properties). The goal of this application is to define the role of the Notch signaling pathway in the peripheral immune response of T lymphocytes.
In Aim 1, the expression patterns of the Notch genes will be analyzed using quantitative PCR.
In Aim 2, the effects of Notch gene expression on T cell fate decisions will be explored by retroviral mediated gene transfer of the Notch genes into primary lymphocytes.
In Aim 3 antigen presenting cells will be engineered to express Notch ligands to explore the role of physiologic Notch signaling on T cell immune responses.
| Adler, Scott H; Chiffoleau, Elise; Xu, Lanwei et al. (2003) Notch signaling augments T cell responsiveness by enhancing CD25 expression. J Immunol 171:2896-903 |
