The overall goal of this proposal is to elucidate the mechanisms which regulate immune senescence. Immune senescence is reflected primarily in the loss of replicative potential of T cells from aged humans. This is the result of both a failure of activated T cells to progress through the G1 phase of the cell cycle in response to the essential growth factor Interleukin 2 and a failure of some cells to become activated and progress from G0 to G1 following the interaction with a mitogen such as the anti-D3 monoclonal antibody OKT3. Transmembrane signaling via the IL2 receptor and the CD3-antigen receptor complex involve similar intracellular pathways which lead to the activation of genes associated with proliferation.
The specific aims of the proposal are: 1. To determine whether a failure of activated T cells from aged humans to progress through the cell cycle in response to IL2 is due to impaired signal transduction via the IL2 receptor. 2. To determine whether a failure of T cells from aged humans to become activated in response to OKT3 binding is due to impaired signal transduction via the CD3-antigen receptor. 3. To determine whether a failure to transduce cell surface signals results in an alteration in the defined pathway of transcription associated with T cell proliferation.
| Demaria, S; Schwab, R; Gottesman, S R et al. (1994) Soluble beta 2-microglobulin-free class I heavy chains are released from the surface of activated and leukemia cells by a metalloprotease. J Biol Chem 269:6689-94 |
| Ding, A; Hwang, S; Schwab, R (1994) Effect of aging on murine macrophages. Diminished response to IFN-gamma for enhanced oxidative metabolism. J Immunol 153:2146-52 |
| Schwab, R; Russo, C; Weksler, M E (1992) Altered major histocompatibility complex-restricted antigen recognition by T cells from elderly humans. Eur J Immunol 22:2989-93 |
| Weksler, M E; Schwab, R (1992) The immunogenetics of immune senescence. Exp Clin Immunogenet 9:182-7 |
| Demaria, S; Schwab, R; Bushkin, Y (1992) The origin and fate of beta 2m-free MHC class I molecules induced on activated T cells. Cell Immunol 142:103-13 |
