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 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. Utilizing these, we uncovered a novel auto-regulatory loop in which IL-2 inhibits its own production that may be an important checkpoint for effector and/or memory production. This inhibitory pathway depends upon the transcriptional repressor Blimp-1.Thus, the major objectives for this proposal are to establish the molecular basis by which IL-2 signaling regulates effector and memory cell programming and to ascertain the biological relevance of Blimp-1-dependent regulation of activated T cells.
The specific aims are: 1) To investigate how IL-2R? signaling regulates individual down-stream molecular targets in activated CD4 and CD8 T cells; 2) to determine the relevance of IL-2R? signaling during the development of immune responses in vivo to nominal antigen and infectious agents; and 3) to directly evaluate the function of IL-2-dependent Blimp-1 in T cell immune responses.
| Castro, Iris; Dee, Michael J; Malek, Thomas R (2012) Transient enhanced IL-2R signaling early during priming rapidly amplifies development of functional CD8+ T effector-memory cells. J Immunol 189:4321-30 |
| Castro, Iris; Yu, Aixin; Dee, Michael J et al. (2011) The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development. J Immunol 187:5170-82 |
| Malek, Thomas R; Castro, Iris (2010) Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33:153-65 |
| Yu, Aixin; Zhu, Linjian; Altman, Norman H et al. (2009) A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30:204-17 |
