in the thymus is both genetically pro-grammed and dependent on extracellular signals that serve as checkpoints and/or drive differentiation; such signals appear to promote death, expansion, further maturation, and the divergence of lineages. Our efforts toward defining these signals are concentrated in four areas: 1) the mechanism responsible for commitment to alpha beta vs. gamma delat lineage; 2) cellular/molecular interactions required for gamma delta T cell development; 3) the nature of interactions inducing positive vs. negative selection; and 4) the mechanisms involved in the CD4/CD8 lineage decision. During development, productive germline rearrangement must occur in the TCR loci before a TCR heterodimer can be expressed. It has been proposed that commitment to the alpha beta or gamma delta lineage takes place prior to or independent of the rearrangement process. Alternatively, the productive rearrangement and/or expression of a particular TCR heterodimer, alpha beta or gamma delta, could determine lineage choice. In many TCRalpha beta transgenic mice, no lymphoid gamma delta T cells develop but, instead, an unusual population of CD4-8- cells appear, bearing the alpha beta transgenic receptor, but with phenotypic and functional properties of gamma delta T cells. The fact that the gamma delta lineage can be """"""""rescued"""""""" with an alpha beta TCR indicates that commitment to the alpha beta vs. gamma delta lineage is not dictated by the class of TCR expressed. To further characterize these lineages, we demonstrated that TCRgamma V to J, as well as TCR deltaV to J, rearrangements occur in the major alpha beta lineage of both TCRalpha beta transgenic and nontransgenic mice; thus, the presence and expression of endogenous or transgenic TCRalpha beta does not prevent rearrangement of the gamma or delta loci. In other alpha beta TCR transgenic mice, endogenous gamma delta TCR is expressed on the same CD4-8- cells that bear the transgenic alpha beta receptor, indicating that expression of an alpha beta TCR does not necessarily preclude expression of a gamma delta TCR. Since inappropriate rearrangements can occur in the wrong lineage, mechanisms must exist to ensure TCR class exclusion. Studies from gamma delta TCR transgenic mice suggest that downregulation of TCR gamma delta RNA message may account for gamma delta TCR exclusion in the alpha beta lineage. To further characterize the extracellular signals that promote gamma delta T cell development, we have used the G8 gamma delta TCR transgenic model. T cells bearing the gamma delta transgene can fully mature in class I-/- mice, indicating that class I-like molecules are not required for maturation/development of gamma delta T cells. Previous results may be attributable to a subtle, negatively selecting ligand. Whether an MHC-driven positive selection step is necessary for gamma delta development is important to understanding the nature of antigen recognition in mature gamma delta T cells and whether antigen recognition is MHC restricted. As the controversy on how T cells make the CD4 vs. CD8 lineage decision continues, we have developed an in vivo model in which we can redirect alpha beta T cells expressing a class II-specific transgenic TCR from the CD4 into the CD8 lineage by eliminating CD4 expression. The fact that these cells can complete their maturation as CD8 cells indicates that this TCR does not require CD4 for class II MHC recognition. Other transgenic alpha beta TCRs show the same developmental pattern to varying degrees, probably depending on their CD4 coreceptor dependence for class II recognition. These results are important for demonstrating that the CD4/CD8 lineage commitment is not strictly dictated by coreceptor usage or by MHC class specificity; instead, a quantitative signaling model is proposed from these and other results.
| 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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