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Chain
* Celltech R&D, Slough, United Kingdom; and
Windeyer Institute of Medical Sciences, London, United Kingdom
Chimeric receptors that include CD28 signaling in series with TCR
in the same receptor have been demonstrated to activate prestimulated human primary T cells more efficiently than a receptor providing TCR signaling alone. We examined whether this type of receptor can also activate resting human primary T cells, and whether molecules other than CD28 could be included in a single chimeric receptor in series with TCR to mediate the activation of resting human primary T cells. Human CD33-specific chimeric receptors were generated with CD28, inducible costimulator, CD134, or CD137 signaling regions in series with TCR signaling region and transfected by electroporation into resting human primary T cells. Their ability to mediate Ag-specific activation was analyzed in comparison with a receptor providing TCR signaling alone. Inclusion of any of the costimulatory signaling regions in series with TCR enhanced the level of specific Ag-induced IL-2, IFN-
, TNF-
, and GM-CSF cytokine production and enabled resting primary T cells to survive and proliferate in response to Ag in the absence of any exogenous factors. Inclusion of CD28, inducible costimulator, or CD134 enhanced TCR-mediated, Ag-specific target cell lysis. Chimeric receptors providing B7 and TNFR family costimulatory signals in series with TCR in the same receptor can confer self-sufficient clonal expansion and enhanced effector function to resting human T cells. This type of chimeric receptor may now be used to discover the most potent combination of costimulatory signals that will improve current immunotherapeutic strategies.
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