Grant: $382,500 - National Institutes of Health - Aug. 28, 2009
No votes have been cast for this award yet
Award Description: The processes by which activated T cells develop into armed effector cells or ultimately persist as long-lived memory cells are becoming better understood. Signal transduction through the IL-2R prominently contributes to these processes. IL-2 promotes optimal T effector responses and is essential for extensive effector cell proliferation and development in vitro. Furthermore, recent data suggest that IL-2 signaling during the primary response may be critical for memory CD8 T cells to proliferate and mediate effector activity upon a recall antigenic challenge. Nevertheless, the molecular mechanism that regulates the effector versus memory programming and the precise contribution by IL-2 to these processes remains largely undefined. During our last grant period, we developed a culture system that models effector and memory T cell development and characterized unique mouse models with selective defects in IL-2R signaling by peripheral T cells. These experimental tools are especially useful for direct analysis of IL-2-dependent molecular events controlling effector and memory programming. From these and other preliminary results, we hypothesize that distinct IL-2R signaling thresholds importantly regulate conventional T cell immune responses. Last, we uncovered that the transcriptional repressor Blimp-1 is a highly IL-2-dependent target that may be an important checkpoint for effector and/or memory production in part as reflected by its role in a novel auto-regulatory loop in which IL-2 inhibits its own production. Thus, the major objectives for this proposal are to establish the molecular basis by which IL-2 signaling regulates primary immune responses, including memory T cell programming, and its consequences on secondary recall immune responses. The specific aims are: 1) To investigate how IL-2Rß signaling regulates individual down-stream molecular targets in activated CD4 and CD8 T cells; 2) to determine the relevance of IL-2Rß signaling during the development of immune responses in vivo; and 3) to directly evaluate the function of IL-2-dependent Blimp-1 in T cells immune responses.
Project Description: The overall purpose of this project is to define the mechanism(s) by which IL-2 functions to promote primary and memory recall responses. During the brief period of this award, which started September 1, 2009, necessary staff has been assigned to the project. Key mouse breeding for specialized models have been expanded to meet the need for future experiments. Studies have been initiated to examine IL-2R¿ signaling threshold variance as a consequence of IL-2 and IL-15. A set of mice have been immunized to assess the quality of the memory response of T cell primed in the presence or absence of IL-2R¿ signaling. These experiments provide the background data to explore role of IL-2R¿-dependent survival vs. programming signaling to develop T cell memory. Samples have also been prepared to determine at a genome-wide level those genes target that are uniquely dependent on IL-2R¿ at the peak of the response and immediately after contraction. Our immediate deliverables are to determine the extent IL-2R¿-dependent targets vary as a consequence of distinct signaling thresholds and to determined whether memory programming is indeed a distinct function of IL-2R¿-dependent signaling. Our long range deliverables are to publish our findings in high quality peer reviewed scientific journals.
Jobs Summary: This ARRA award has permitted retention of 1.5 FTEs. 1FTE is a Post-doctoral Associate and 0.5 is a Research Associate. Both are highly experienced individuals with skills specific for the planned work (Total jobs reported: 2)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 28, 2009. Help expand these official descriptions using the wiki below.