The goal of our studies is to identify the key cellular populations which are involved in the anti-viral and/or anti-tumor cell-mediated cytotoxicity in vivo and to develop new experimental strategies to target these subpopulations of lymphocytes for immunomodulation. This will eventually lead to the new treatments of autoiummune diseases and/or cancer. A) Cytotoxic CD8+T -lymphocytes (CTL) were considered to be an important part of anti-viral and anti-tumor immunity due to their ability to recognize and to kill specific target cells.However,very low percentage or no CD8+ CTL were found in recently developed MHC class I-deficient( b2m-/- ) mice with no significant effect on the development or survival of such animals. This raised doubts about the functional significance of CD8+ CTL.If CD8+ CTL were proven to be irrelevant in vivo,then the conceptual framework of immunomodulation had to be reconsidered. To clarify the role of CD8+CTL in in vivo tumor rejection we asked if the b2m-/- mice are able to reject intraperitonealy injected tumor cells ( as was shown to be the case with normal mice) and what is the cellular composition of peritoneal exudates leukocytes (PEL) from such mice. It is found that b2m-/- mice do reject i.p. injected MHC class I bearing tumor cells. Surprisingly, analysis of PEL CTL obtained from i.p. tumor injected b2m-/- mice revealed the presence of a large proportion of functional, tumor destroying CD8+, CD4-, alpha betaTCR+, CD3+, Thy-1+, MHC class-I-negative CTL with strong MHC class I directed cytotoxic activity. These results reconfirm the anti-tumor role of CD8+CTL, call for the careful studies of local accumulation of CD8+ CTL in b2m-/- mouse model and suggest the redundancy of MHC class I expression in normal animals. B) During our studies of the role of extracellular ATP in CTL-mediated cytotoxicity we established that it is MgATP-2 and not ATP4-, that may be a """"""""messenger"""""""" in CTL-target cell interactions.
| Kojima, H; Toda, M; Sitkovsky, M V (2000) Comparison of Fas- versus perforin-mediated pathways of cytotoxicity in TCR- and Thy-1-activated murine T cells. Int Immunol 12:365-74 |
