Embodiments of the disclosure include methods and compositions forimmunotherapy that comprise allogeneic cellsthat are able to be universally tolerated in host individuals In specificembodiments the cells have reduced expression of endogenousbeta2-microglobulin (B2M) and/or MHC class II-associated invariant chain (I1),and in particular cases the cells are NKT cells thatlack the ability to damage host tissues, have much reduced recognition by hostimmune cells, and surprisingly avoid destruction byhost NK cells In some embodiments, B2M- and/or II-targeting molecules areengineered to be expressed in combination (includingwithin a single construct) with recombinantly engineered receptors, forexample, for a one-hit generation of universally toleratedoff-the-shelf immunotherapy
