These studies have attempted to deal with the paradox of how signaling through a given TCR (T cell antigen receptor) can mediate both the positive and negative selection events that occur during T cell development. Several of our investigations suggest that the affinity of the interaction determines developmental fate. In male mice which express both transgenic CD8 and anti-HY TCR, cells bearing the transgenic TCR but low levels of endogenous CD8 are clonally deleted, whereas the CD8 transgene does not lead to deletion of the CD4-8- TCR+ cells. The results suggest that the mice possess both deletable and nondeletable lineages. The CD8 transgene also affects the ultimate fate of T cells developing in anti-Ld TCR transgenic mice. In H-2b mice, where only positive selection is evident, introduction of the CD8 transgene results in negative selection. Since the CD8 coreceptor strengthens the TCR-MHC interaction, it would appear that a change in affinity controls the developmental outcome. Additional results suggest that positive and negative selection may not be ordered. If appropriate chimeras are constructed, such that positive selection cannot occur, clonal deletion is still observed. This result rules out a maturational requirement (as a result of positive selection) in order for negative selection to occur. Using two transgenic mouse systems, one with a class I-restricted TCR, and one with a class II restricted TCR, antigen presentation was targeted to the thymic epithelium only by using radiation/bone marrow chimeras. In both of these systems, the thymic epithelium is able to mediate clonal deletion of the transgenic receptor-bearing T cells. Since epithelial cells can mediate both positive and negative selection events, these results also support a model of development that invokes differential signaling through different strengths of interaction. The thymus is able to induce tolerance to self antigens by a nondeletional mechanism which was observed when the relevant antigen is expressed only on the epithelium. Adoptive transfers of the nonresponsive cells into hosts that lack the self antigen results in a reversal of the nonresponsive state. Thus, persistence of antigen is required to maintain this nondeletional form of in vivo tolerance.
| 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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