Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes.
OBJECTIVE
Cytokine-induced killer cells (CIK) are CD3(+)CD56(+) T cells with natural killer (NK)-like cytotoxic activity used for the immunotherapy of tumors. We aimed to fully characterize CIK cells and define their ontogeny.


METHODS
CIK were generated in vitro by stimulation of peripheral blood mononuclear cells or T-cell subsets with interferon-gamma, anti-CD3 and interleukin-2. They were fully characterized in terms of phenotype, cytotoxic activity, and gene expression with respect to circulating CD3(+)CD56(+) cells, NK cells, and CD56(-) T cells present in CIK cultures.


RESULTS
We demonstrate that CIK are terminally differentiated CD8 T cells that derive from proliferating CD3(+)CD56(-)CD8(+) T cells. They express polyclonal T-cell receptor Vbeta chains and have acquired CD56, NKG2D, and large granular lymphocyte morphology, but lack expression of most NK-specific activating (NKp30, NKp44, NKp46) and inhibitory (KIR2DL1, KIR2DL2, KIR3DL1, NKG2A, CD94) receptors, and can kill K562 targets. Circulating CD3(+)CD56(+) cells are also CD8(+)CD16(-), but are oligoclonal, poorly cytotoxic for K562, and express lower levels of CD56 and NKG2D. Gene profiling of CIK, CD56(-) T and NK cells present at the end of culture shows that differences are much more limited between CIK and CD56(-) T compared to CIK and NK cells. Most of the genes upregulated in CIK cells compared to CD56(-) T cells are part of the tumor necrosis factor gene network.


CONCLUSIONS
The CIK phenotype, that is CD45RA(+), CCR7(-), CD62L-weakly positive, CD11a(+), CD27(+), CD28(-), macrophage inflammatory protein 1alpha(+), perforin(+), Fas ligand(+) coincides almost exactly with that described for the T RA(+) effector memory CD27 single positive subset of terminally differentiated human memory T cells.
Franceschetti
Marta
M
Laboratory of Cellular Therapy G. Lanzani, USC of Hematology, Ospedali Riuniti Bergamo, Bergamo, Italy.
Pievani
Alice
A
Borleri
Gianmaria
G
Vago
Luca
L
Fleischhauer
Katharina
K
Golay
Josée
J
Introna
Martino
M
D000943:Antigens, Differentiation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods; D020014:K562 Cells; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy
D000943:Antigens, Differentiation