T cells gene-engineered with DAP12 mediate effector function in an NKG2D-dependent and major histocompatibility complex-independent manner.
NKG2D is an important activating/co-stimulatory receptor harnessed by NK and T cells in immune surveillance. In contrast to NK cells, T cells fail to express the activation-signaling molecule DAP12 even when activated and, therefore, ligation of NKG2D alone is insufficient to induce T cell cytolytic function. To test whether we could endow T cells with NK cell-like effector function, we have engineered DAP12 into T cells by retroviral transduction (T-DAP12). T-DAP12 cells were demonstrated to specifically secrete interferon-gamma following receptor ligation and to mediate potent and specific lysis of the NKG2D ligand (NKG2D-L) (Rae-1beta) expressing MHC class I-deficient and class I-sufficient tumors. To circumvent the inability of T-DAP12 cells to proliferate following NKG2D ligation by Rae-1beta expressing tumors, DAP12 was engineered into OT-1 cells with an endogenous T cell receptor specific for chicken ovalbumin peptide (amino acids 257-264). Importantly, following a period of proliferation through endogenous T cell receptor ligation, OT-1-DAP12 cells retained specificity against NKG2D-L expressing major histocompatibility complex class I-deficient tumor. In adoptive transfer experiments, T-DAP12 cells enhanced the survival of NK cell-depleted RAG-1-deficient mice inoculated with RMA-S-Rae-1beta but not parental RMA-S tumors. Overall, this study demonstrated the significant potential of suppressing tumors and other cellular targets expressing NKG2D-L by endowing T cells with innate NK cell-like function.
Teng
Michele W L
MW
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia.
Kershaw
Michael H
MH
Hayakawa
Yoshihiro
Y
Cerutti
Loretta
L
Jane
Stephen M
SM
Darcy
Phillip K
PK
Smyth
Mark J
MJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002645:Chickens; D003001:Cloning, Molecular; D016207:Cytokines / Q000096:biosynthesis; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D005818:Genetic Engineering / Q000379:methods*; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000628:therapy; D010047:Ovalbumin / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D000939:Epitopes; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010455:Peptides; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C484963:Tyrobp protein, mouse; D007371:Interferon-gamma; D010047:Ovalbumin