Human CD4+ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC 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.[1]References
- Human CD4+ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC Class II Restriction by an Antibody-Like Immunoreceptor. Hombach, A., K??hler, H., Rappl, G., Abken, H. J. Immunol. (2006) [Pubmed]
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