T W Mak

Less Mortality but More Relapses in Experimental Allergic Encephalomyelitis in CD8-/- Mice

Mice lacking in CD8 were generated from homologous recombination in embryonal stem cells at the CD8 locus and bred with the experimental allergic encephalomyelitis (EAE)susceptible PL/J H-2u through four backcross generations to investigate the role of CD8+ T cells in this model of multiple sclerosis. The disease onset and susceptibility were similar to those of wild-type mice. However, the mutant mice had a milder acute EAE, reflected by fewer deaths, but more chronic EAE, reflected by a higher frequency of relapse. This suggests that CD8+ T lymphocytes may participate as both effectors and regulators in this animal model.

Developmental Studies of Brca1 and Brca2 Knock-Out Mice

In humans, the inheritance of mutations in thebreast cancer susceptibility genes BRCA1 and BRCA2increases the risk of developing breast and ovariancancer. To study their biological function and to create animal models for these cancer susceptibilitygenes, several strains of mice mutated in the homologousgenes Brca1 and Brca2 have been generated by genetargeting. Analyses of these “knock-out” mouse mutants have provided invaluableknowledge about the function of these genes. Brca1 andBrca2 null mutants are similar in phenotype: mutationsin both genes result in embryonic lethality and thedeveloping embryos show signs of a cellular proliferationdefect associated with activation of the p53 pathway.The significance of this activation, as well as the roleof these cancer susceptibility genes in DNA damage repair, is discussed.

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.