During T cell development, thymocytes that are able to recognize self MHC are signalled to mature (positive selection), whereas those capable of self reactivity are selected to die (negative selection). Many of these studies deal with the paradox of how signaling resulting from a specific TCR-MHC interaction can determine the positive or negative selection events. Several investigations involving TCR transgenic mice reveal that distinct thymic antigen presenting cells are probably not responsible for these alternate forms of selection. Instead, they suggest that it is the affinity of the TCR-MHC interaction that controls the developmental outcome. Increasing the coreceptor expression (through a CD8 transgene) is able to enhance TCR recognition of MHC, and alter net selection effects from positive to negative. Likewise, enhancing MHC expression by increasing MHC gene dosage can alter developmental fate. Thymic selection can, in some cases, be determined also by tissue-specific peptides presented only on thymic epithelium. Our previous studies indicated that the thymus is able to induce tolerance to self antigens not only by deletional mechanisms but also by clonal inactivation (anergy). Transfer of the nonresponsive cells into hosts that lack the self antigen or into in vitro culture results in a reversal of the nonresponsive state, indicating that antigen is required to maintain this nondeletional form of in vivo tolerance. The mechanism responsible for commitment to the alphaBeta or gamma delta lineage has also been approached using TCR transgenic mice. If TCR-beta transcriptional regulatory elements are used to direct expression of the TCRalphaBeta transgenes, gamma delta T cells do not appear. Instead, there appears a CD4-8- cell bearing the TCR-alphaBeta transgenic receptor, but with the developmental, phenotypic, and functional properties of gamma delta T cells. These results suggest that T cell functions may be associated with a specific lineage, irrespective of TCR usage. These findings have led to an investigation of the role of TCR transcriptional regulatory elements in lineage development.
| 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
