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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2364-2371
GENE THERAPY
Integrated src kinase and costimulatory activity enhances signal
transduction through single-chain chimeric receptors in T
lymphocytes
Terrence L. Geiger,
Phuong Nguyen,
David Leitenberg, and
Richard A. Flavell
From St Jude Children's Research Hospital, Memphis,
TN; University of Tennessee School of Medicine, Memphis, TN; George
Washington University, Washington, D.C.; Yale University School of
Medicine, New Haven, CT; and Howard Hughes Medical Institute, New
Haven, CT.
Adoptive immunotherapy using receptor-modified T lymphocytes has
shown promise in preclinical studies for the treatment of infectious
and malignant diseases. These modified T cells express chimeric
receptors that link ligand recognition and signal transduction domains
in a single gene product. Typically, a single chain Fv fragment is
genetically attached to the cytoplasmic domain of the T-cell receptor
(TCR)  chain. Modulating the signaling characteristics of chimeric
receptors will be important for their application to human
immunotherapy. It was hypothesized that linking coreceptor and
costimulatory signaling motifs together with the signaling domain
will enhance receptor function. The present study compares signaling characteristics of 9 single-chain receptors consisting of the
H-2Kb extracellular and transmembrane domains and various
combinations of T cell signal transduction domains. Signal transduction
regions studied include the TCR chain, the CD4 coreceptor, the lck
protein tyrosine kinase, and the CD28 costimulatory receptor.
Biochemical characteristics of the receptors, analyzed using
calcium flux, receptor, and ZAP-70 phosphorylation, and lck
association may be predicted from the known functions of receptor
constituents. The combination of together with coreceptor and
costimulatory function in a single receptor maximizes chimeric receptor
sensitivity and potency. Combining with either the costimulatory or
coreceptor function independently also enhances receptor function,
though to a lesser extent. It is therefore possible to link TCR,
coreceptor, and costimulatory activities in a single functional entity
using modular domains. Such receptors demonstrate distinct signaling properties and should prove useful in the development of chimeric receptors for therapeutic purposes.
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