Valerie A. Wallace

Requirement for tyrosine kinase p56lck for thymic development of transgenic gamma delta T cells.

The Src-related protein tyrosine kinase p56lck is essential for antigen-specific signal transduction and thymic maturation of T cells that have an alpha beta T cell receptor (TCR), presumably by physical association with CD4 or CD8 molecules. To evaluate the requirement for p56lck in the development of T cells that have gamma delta TCRs, which generally do not express CD4 or CD8, p56lck mutant mice were bred with TCR gamma delta transgenic mice. Few peripheral cells that carried the transgenes could be detected in p56lck-/- mice, although 70 percent of thymocytes were transgenic. Development of transgenic gamma delta+ thymocytes was blocked at an early stage, defined by interleukin-2 receptor alpha expression. However, extrathymic development of CD8 alpha alpha+ TCR gamma delta+ intestinal intraepithelial lymphocytes appeared to be normal. Thus, p56lck is crucial for the thymic, but not intestinal, maturation of gamma delta T cells and may function in thymic development independently of CD4 or CD8.

The Role of p56ICk and p59fyn Tyrosine Kinases and CD45 Protein Tyrosine Phosphatase in T-cell Development and Clonal Selection

Mechanisms governing positive and negative T-cell selection are critically dependent on the physical interaction between the anti gen-specific T-cell receptor (TCR) on developing thymocytes and MHC molecules expressed on thymic stromal cells. Recognition of MHC class I molecules by the TCR commits thymocytes to the CD8+ lineage whereas interactions with MHC class II molecules determine the generation of CD4^ T lymphocytes (Zinkernagel et al. 1978, Kisielow et al. 1988, Sha etal. 1988, Benoist et al. 1989, Berg et al. 1989, Bill etal. 1989, Fowlkes et al. 1989, Schwartz 1989, Blackman et al. 1990, von Boehmer 1990, 1993). Recognition of self MHC molecules expressed in the thymus by immature thymocytes and subsequent differentiation into CD4̂ or CD8^ T cells are the basis of positive selection. Thymocytes expressing TCRs which recognize self antigens with high affinity are clonally deleted to maintain self tolerance. Positive commitment to either functional T-cetl lineage can be instructive or stochastic (Robey et al. 1991. von Boehmer etal. 1993, Chan etal. 1993, Davis et al. 1993). Besides the antigen-specific TCR, CD4 and CD8 coreceptors are crucial for positive selection of cytotoxic (FungLeung et al. 1991) and helper T cells (Rahemtulla et al. 1991). Interactions between developing thymocytes and thymic stromal cells must

CD4, CD8 and tyrosine kinases in thymic selection

Analysis of T-cell development in transgenic and gene-deficient mice suggests that the co-receptor function of CD8 is essential for positive selection. Recent data also demonstrate that the requirement for CD4 and CD8 in negative selection of T cells is not absolute and may be regulated by T-cell receptor affinity for the deleting ligand, an interpretation consistent with the affinity model of thymic selection. In addition to its association with CD4 and CD8, it appears that p56lck is also important during the early stages of thymic development.

Transgenic Mice as an in vivo Model for Self-Reactivity

This work presents descriptions of transgenic models that address how the immune system copes with a genetically-engineered, self-reactive situation. Descriptions of the prototypic systems are provided, and the differences and nuances of related transgenic models are compared and contrasted.

5 – T Cell Development in CD4, CD8, and p56lck Gene-Targeted Mice

Publisher Summary Positive selection of major histocompatibility complex (MHC) class I- and class II-restricted T cells is dependent on the coreceptor function of CD8 and CD4. In most cases, the coreceptor function of CD8 is required for clonal deletion mediated by self peptides presented by MHC class I molecules. In some instances, clonal deletion mediated by MHC class I determinants can occur in the absence of CD8 expression. Clonal deletion mediated by MHC class II-associated retro viral superantigens (SAGs) can occur in the absence of CD4 expression. However, T cells with low affinity for SAG require CD4 for clonal deletion. Therefore, some T cell receptors (TCRs) might have sufficient affinity for the deleting ligand and might not require CD4 or CD8 expression for clonal deletion, an interpretation consistent with the affinity model of T cell selection. The protein tyrosine kinase p56lck plays a role in signal transduction via coreceptors during selection. However, coreceptor-derived signals through lck are not required during thymic development and can be compensated for by the over-expression of coreceptors. The function of p56lck during thymic development is complex because this protein tyrosine kinase is required in a non-CD4/CD8-associated manner during early stages of T cell differentiation.