Embodiments of the disclosure include methods and compositions for immunotherapy that comprise allogeneic cells that are able to be universally tolerated in host individuals. In specific embodiments the cells have reduced expression of endogenous beta2-microglobulin (B2M) and/or MHC class II-associated invariant chain (Ii), and in particular cases the cells are NKT cells that lack the ability to damage host tissues, have much reduced recognition by host CD8 and/or CD4 T cells, and surprisingly avoid destruction by host NK cells. In some embodiments, B2M- and/or Ii-targeting molecules are engineered to be expressed in combination (including within a single construct) with synthetic receptors for a one-hit generation of universally tolerated off-the-shelf immunotherapy.
