Involvement of T lymphocyte subsets in the rejection of murine tumors by syngeneic or autologous hosts

The aim of this thesis is to study the requirement of CD4+ and CD8+ T Iymphocyte subset, CD28 costimulatory molecule and p56kk for the rejection of syngeneic tumor grafts, and the autochthonous tumors induced by Moloney murine sarcoma virus. It also addresses the role of CD4+ and CD8+ T subsets with regard to the polyomavirus persistence and tumor development. CD4-, CD8-, CD8-/4-, CD28- and p56kk-knockout mice were used as syngeneic or autologous animal models.

In tumor transplantation rejection experiment, deficiency of either CD8+ or CD4+T cells abrogated the protective immunity against ALC Iymphoma grafts, but not against MC57X fibrosarcoma. MC57X-specific TNF-a release was induced in preimmunized syngeneic CD8-/- or CD4-/- mice. MMSV-induced primary sarcoma regressed in all CD4-/- mice, but about half of CD8-/-mice developed progressive tumors. MMSV tumor regression was abolished in CD8-/-4-/-double knockout mice. Deficiency of B cells and antibody production did not affect MMSV tumor regression. When adult mice were infected with polyomavirus, deficiency of either CD4+ or CD8+ T subset did not affect the clearance of the virus, but the viral persistence was established in CD4-/-8-/- double knockout mice. When newborn mice were infected, polyoma tumor incidence was significantly increased in CD4-/-8-/- double knockout mice.

ALC and MC57X tumors were rejected by preimmunized syngeneic CD28-/ mice. MMSV-induced primary sarcoma regressed in CD28-/- hosts. However, the spontaneous regression of B7-transfected EL-4 Iymphoma was abrogated by CD28 deficiency. Tumor- or virus-specific CTLs, as well as TNF release, were able to be induced in the CD28 knockout mice. In p56kk-deficient mice, protective immunity against MC57X was abolished, and MHC-incompatible or minor-different skin grafts were tolerated. Natural killer remains normal. Taken together, the requirement of CD4+, CD8+ T subsets and CD28 co-stimulation is differential, depending on the type of tumor and the anti-tumor immune response.