We sought to develop a better understanding of the T cells involved in the human allogeneic immune response, in order to eventually engineer a donor graft with reduced GVHD-mediating potential, without ablating general immune competence. Prior studies reported that all the activated CD4+ T cells responding to a specific antigen challenge reside within the CD4high population expressing high levels of membrane CD4. We identified a new population of activated CD8+ T cells that developed during an in vitro allogeneic immune response, along with the allo-activated CD4high T cell population. Analogous to activated CD4+ T cells, this new T cell population was distinguished by up-regulated CD8 (and CD38) expression (CD8highCD38+). In accordance with Martins et al. (Blood 2004, 104:3429), we found that the depletion of the CD4highCD38+ population resulted in reduced 2o response to the original 2nd party stimulators. In contrast, depletion of the CD8highCD38+ population resulted in an increased 2o response to 2nd party cells, with no change in the response to 3rd party or CMV antigens. Elevated numbers of CD8highCD38+ T cells potently reduced the 1o and 2o responses to 2nd party, but not to 3rd party cells or CMV antigens. The complementary, non-activated CD8normalCD38− T cell population had no inhibitory effect. Importantly, we found that
CD8highCD38+ T cells mediated both a specific cytotoxic response (that could be inhibited by the pan-caspase inhibitor, Z-VAD), and a specific suppressive response toward the original 2nd party stimulators (that was not affected by Z-VAD), and within this CD8highCD38+ population, there was a subpopulation of cytotoxic T cells (perforin+LAMP1+CD56+CD11b+CD11c+) and a subpopulation of non-cytotoxic T cells.
Furthermore, we found that although CD8highCD38+ T cells differentially expressed CD28, both CD8highCD38+CD28− and CD8highCD38+CD28− T cells mediated a cytotoxic as well as a suppressor T cell response toward the original 2nd party cells (different from the published suppressive function of CD8+CD28− T cells observed by Liu et al, Int Immunol 1998, 10:775). Upon separation of cytotoxic CD8highCD38+ T cells from suppressor CD8highCD38+ T cells, we will explore the GVHD potential of these 2 novel activated CD8high T cell subpopulations, in a sensitive in vivo xenograft model for GVHD using NOD/SCID/IL2Rγnull immunodeficient mice.
Regulation of phosphoinositide kinases in T cells. Evidence that phosphatidylinositol 3-kinase is not a substrate for T cell antigen receptor-regulated tyrosine kinases.
