A major aim of this project is to identify the signals that control cell fate decisions in developing T cells. Our primary focus in the past year has been on the role of the T cell antigen receptor (TCR) and how it works together with other developmental cues to control maturation, proliferation, death, and lineage commitment. In these studies we have determined that: * The nature of the TCR signal (__ vs. __ in the _____ lineage choice and the involvement of CD4 vs. CD8 in the CD4/CD8 lineage decision) imposes a bias on the lineage choice. * Signals through the highly conserved, transmembrane receptor, Notch, also biases these lineage decisions. * A constitutively active form of Notch can override the bias normally imposed by the TCR signal, suggesting that the two signaling systems may act in concert to specify cell fate. * Cell-cell interactions between neighboring thymocytes influence __ versus __ T cell fate. * The expression of some TCR-associated signal transducing proteins are developmentally regulated in maturing T cells. * __ T cells require interactions with a self-protein, MHC, for maturation and survival (positive selection). If this interaction produces very strong signals inside the cell, cell death rather than maturation will occur (negative selection). Our results indicate that for those cells that survive, it is also the relative strength of the interaction that determines whether a cell will become a CD4 or CD8 T cell. * Once the lineage choice is made, additional mechanisms operate to insure that the appropriate T cell receptor is expressed in the appropriate lineage. * Whether a developing T cell is positively or negatively selected is affected by the quantity of MHC+peptide ligand and the cell type expressing the selecting ligand.
| Laky, Karen; Fowlkes, B J (2007) Presenilins regulate alphabeta T cell development by modulating TCR signaling. J Exp Med 204:2115-29 |
| Laky, Karen; Fleischacker, Christine; Fowlkes, B J (2006) TCR and Notch signaling in CD4 and CD8 T-cell development. Immunol Rev 209:274-83 |
| Broussard, Christine; Fleischacker, Christine; Fleischecker, Christine et al. (2006) Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25:93-104 |
| Uehara, Shoji; Hayes, Sandra M; Li, LiQi et al. (2006) Premature expression of chemokine receptor CCR9 impairs T cell development. J Immunol 176:75-84 |
| Laky, Karen; Fowlkes, B J (2005) Receptor signals and nuclear events in CD4 and CD8 T cell lineage commitment. Curr Opin Immunol 17:116-21 |
| Canelles, Matilde; Park, Melissa L; Schwartz, Owen M et al. (2003) The influence of the thymic environment on the CD4-versus-CD8 T lineage decision. Nat Immunol 4:756-64 |
| Fowlkes, B J; Robey, Ellen A (2002) A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development. J Immunol 169:1817-21 |
| Feng, Chiguang; Woodside, Kenneth J; Vance, Barbara A et al. (2002) A potential role for CD69 in thymocyte emigration. Int Immunol 14:535-44 |
| Hayes, Sandra M; Laky, Karen; El-Khoury, Dalal et al. (2002) Activation-induced modification in the CD3 complex of the gammadelta T cell receptor. J Exp Med 196:1355-61 |
| Pellegrini, Luca; Passer, Brent J.; Canelles, Matilde et al. (2001) PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2. J Alzheimers Dis 3:181-190 |
Showing the most recent 10 out of 11 publications
