Mature T cells develop in the thymus through a series of differentiation events that are either genetically programmed or dependent on external signals provided in the microenvironment. Some of these signals induce death or maturation, promote proliferative phases, or are responsible for the divergence of lineages. Our major efforts focus on gammadelta/alphabeta lineage commitment, the requirements for gammadelta development, selective events in the alphabeta lineage, and the mechanism of the CD4/CD8 lineage decision. Our studies in alphabeta T cells show that-for some T cells-more than one MHC may be used to drive the cell to full maturation, supporting the notion that positive selection is a multistep event. Somewhat surprisingly, the elimination of CD4 in mice bearing a transgenic class II-dependent TCR altered the lineage decision such that significantly more cells matured as CD8 T cells. These data, taken together with other studies showing that constitutive expression of CD8 transgene is very inefficient at promoting the maturation of CD4+ cells with class I MHC-specific TCR, argue against a model in which lineage decisions are made irrespective of coreceptor usage. Investigations of gammadelta T cell development indicate that the type of MHC allele can determine the death or survival and functional capacity of mature cells. The maturation of some gammadelta T cells appears to require MHC displayed on hematopoietic cells rather than on thymic epithelium. A discrepancy exists in that mature gammadelta cells are present in lymph nodes and not the thymus of beta2m-deficient mice. These studies are a necessary prerequisite to identifying the selecting ligand for gammadelta T cells, if it exists. In TCR alphabeta transgenic mice, a population of CD4-8- T cells is generated bearing the transgenic TCR with phenotypic and functional properties of gammadelta T cells, suggesting that gammadelta/alphabeta lineage commitment may occur independent of TCR gene rearrangement. Both gammadelta and alphabeta antigen receptors exist on some cells in the epidermis, while gammadelta TCR is not observed at all in the thymus, the reproductive epithelium or other lymphoid organs. These results indicate that the suppression of endogenous gammadelta TCR by the expression of transgenic TCRalphabeta is related to the timing of TCR gene rearrangement and/or expression. Some gamma rearrangements occur in both CD4-8- and CD4+8- subpopulations of TCRalphabeta transgenic mice; whether these are quantitatively different or differ in the frequency of productive rearrangement is under investigation. The latter results should bear on the nature of lineage commitment and allelic exclusion in gammadelta T cells.
| 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 |
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