Human CD4+ T cells lyse target cells via Granzyme/Perforin upon circumvention of MHU class II restriction by an antibody-like immunoreceptor

Immune elimination of tumor cells requires the close cooperation between CD8(+) CTL and CD4(+) Th cells. We circumvent MHC class II-restriction of CD4(+) T cells by expression of a recombinant immunoreceptor with an Ab-derived binding domain redirecting specificity. Human CD4+ T cells grafted with an immunoreceptor specific for carcinoembryonic Ag (CEA) are activated to proliferate and secrete cytokines upon binding to CEA(+) target cells. Notably, redirected CD4(+) T cells mediate cytolysis of CEA(+) tumor cells with high efficiencies. Lysis by redirected CD4(+) T cells is independent of death receptor signaling via TNF-alpha or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-alpha. CD4(+) T cells redirected by Ab-derived immunoreceptors in a MHC class II-independent fashion substantially extend the power of an adoptive, Ag-triggered immunotherapy not only by CD4(+) T cell help, but also by cytolytic effector functions. Because cytolysis is predominantly mediated via granzyme/perforin, target cells that are resistant to death receptor signaling become sensitive to a cytolytic attack by engineered CD4(+) T cells.