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Thymic heterotypic cellular complexes in gene-targeted mice with defined blocks in T cell development and adhesion
A J Oliveira-dos-Santos1, J M Penninger, T Rieker-Geley
1Institute for General and Experimental Pathology, Medical School, University of Innsbruck, Austria.
European Journal of Immunology
|October 1, 1998
Summary
Thymic nurse cell (TNC) and rosette (ROS) complex formation depends on T cell development stages. Early T cell development is crucial for TNCs, while ROS formation requires a functional T cell receptor beta chain and CD4 expression.
Area of Science:
- Immunology
- Developmental Biology
- Cell Biology
Background:
- Thymocytes form multicellular complexes with thymic stromal cells, including thymic nurse cells (TNCs) and rosettes (ROS).
- The precise developmental stages and molecular interactions governing these heterotypic complexes in vivo remain incompletely understood.
Purpose of the Study:
- To investigate the role of T cell differentiation checkpoints in the in vivo formation of thymic heterotypic complexes (TNCs and ROS).
- To elucidate the contribution of specific T cell developmental stages and adhesion molecules to thymocyte-stromal cell interactions.
Main Methods:
- Utilized genetically engineered mutant mice with defined blocks at various T cell development stages (RAG-1-/-, TCRbeta-/-, p56lck-/-, CD8-/-, IFN regulatory factor-1-/-, CD45-/-, TCRalpha-/-, CD30-/-, CD4-/-, MHC class II-/-).
- Analyzed the formation of TNCs and ROS in these mutant mice.
- Investigated the effect of a human CD4 transgene in CD4-/- mice.
- Examined the role of adhesion molecules CD44 and LFA-1.
Main Results:
- RAG-1-/-, TCRbeta-/-, and p56lck-/- mutations abrogated ROS formation, indicating a requirement for T cell receptor rearrangement and expression.
- TNC formation was partially reduced in RAG-1-/- mice but unaffected by TCRbeta and p56lck mutations, suggesting TNCs form earlier in development.
- CD4-/- mice exhibited significantly reduced TNC and ROS formation, particularly ROS with dendritic cells, which was rescued by CD4 transgene expression.
- Genetic blocks in CD8 lineage commitment and T cell selection did not impact complex formation.
- CD44 and LFA-1 were shown to cooperate in thymic microenvironment formation.
Conclusions:
- TNC formation represents an early thymocyte-stromal interaction, while ROS formation is dependent on later T cell development stages, including functional TCRbeta expression.
- CD4 plays a critical, previously unrecognized role in both TNC and ROS formation, particularly ROS with dendritic cells.
- Adhesion molecules CD44 and LFA-1 are important for establishing thymocyte-stromal interactions within the thymic microenvironment.