Wai-Ping Fung-Leung

CD8 is needed for development of cytotoxic T but not helper T cells

Abstract A mutant mouse strain without CD8 (Lyt-2 and Lyt-3) expression on the cell surface has been generated by disrupting the Lyt-2 gene using embryonic stem cell technology. In these mice, CD8 + T lymphocytes are not present in peripheral lymphoid organs, but the CD4 + T lymphocyte population seems to be unaltered. Cytotoxic response of T lymphocytes from these mice against alloantigens and viral antigens is dramatically decreased. Proliferative response against alloantigens and in vivo help to B lymphocytes, however, are not affected. These data suggest that CD8 is necessary for the maturation and positive selection of class I MHC restricted cytotoxic T lymphocytes but is not required on any of the intermediate thymocyte populations (CD8 + CD4 − TcR − or CD4 + CD8 + TcR low ) during the development of functional class II MHC restricted helper T cells.

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.

EMBRYONIC STEM CELLS AND HOMOLOGOUS RECOMBINATION

Mice with defined genetic defects can now be generated using gene targeting technology based on the successful generation of mouse embryonic stem cells with the potential for germ line transmission, and the development of methods for detection of homologous recombination.

Requirement of the CD8+ or CD4+ T lymphocyte subsets for the rejection of lymphoma and fibrosarcoma grafts studied in gene knockout hosts

Rejections of the retrovirus induced lymphomas (ALC and RBL-5) and the methylcholanthrene (MCA) induced fibrosarcoma (MC57X) grafts were tested in syngeneic CD8 and CD4 single and double knockout C57BL/6 mice. The results with the lymphomas showed that the CD8+ T cell deficiency prevented the development of rejection response induced by immunization. Deficiency of the CD4+ T subset abrogated also the rejection of ALC. Immunity against the fibrosarcoma cells developed in both type of single knockout mice, but not in the ones which lacked both CD4+ and CD8+ T cells. Thus CD8+ T cells were required for rejection of the lymphoma cells, while the CD4+ T cells only mediated a weak response. In absence of CD8+ T cells, CD4+ T cells were sufficient to reject the fibrosarcoma cells.

Embryonic stem cells and homologous recombination

Mice with defined genetic defects can now be generated using gene targeting technology based on the successful generation of mouse embryonic stem cells with the potential for germ line transmission, and the development of methods for detection of homologous recombination.