T cells specific for CD1-restricted self-lipids could play a role in cancer immune surveillance, where self-antigens are the targets of immune responses. The lack of polymorphism of CD1 molecules and their expression on mature leukocytes make also attractive adoptive immunotherapy with CD1 self-reactive T cells in the context of stem cell transplantation for hematological malignancies. Recently, we showed that a large number of AML express CD1c and demonstrated that a group of CD1c self-reactive T cells recognizes methyl-lysophosphatidic acids (mLPA), a novel class of self-lipid antigens that accumulate in AML blasts and target T-cell destruction of leukemia cells in vitro and in mouse xenograft models. To gain insight into mechanisms, efficacy and safety of adoptive cell therapy for AML with mLPA-specific T cells, we generated a library of lentiviral vectors encoding a panel of human mLPA-specific TCR. The transfer of these TCRs into primary human T cells generates large numbers of effectors specifically redirected against CD1c-expressing malignant targets. The effects of the transfer of TCR-engineered T cells on CD1c-dependent control of leukemia xenografts is being addressed in humanized NSG mice. Furthermore, mLPA-specific immunesurveillance of CD1c-expressing tumor cells is also investigated in newly generated transgenic mice expressing CD1c (CD1c Tg), using mouse T cells transduced with human mLPA-specific TCRs and CD1c-expressing mouse leukemia or lymphoma cells. The CD1c Tg mice were generated by micro-injecting a BAC containing group 1 CD1 and CD1e genes. The mice express CD1 proteins in monocyte, DCs and B cells, similar to human cells; however, thymocytes are negative. To overcome the problem, Tg mice expressing CD1c on T cells under the proximal Lck promoter were generated. Double pLck-BAC CD1c Tg mice harbour peripheral T cells that, upon polyclonal activation in vitro, recognize human CD1c-expressing malignant cells, suggesting the selection of a CD1c self-reactive T cell repertoire