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Titolo:
Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes
Autore:
Geiger, TL; Nguyen, P; Leitenberg, D; Flavell, RA;
Indirizzi:
St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA St Jude Childrens Hosp Memphis TN USA 38105 Pathol, Memphis, TN 38105 USA Univ Tennessee, Sch Med, Memphis, TN 38163 USA Univ Tennessee Memphis TN USA 38163 essee, Sch Med, Memphis, TN 38163 USA George Washington Univ, Washington, DC USA George Washington Univ Washington DC USA ington Univ, Washington, DC USA Yale Univ, Sch Med, New Haven, CT USA Yale Univ New Haven CT USAYale Univ, Sch Med, New Haven, CT USA Howard Hughes Med Inst, New Haven, CT 06510 USA Howard Hughes Med Inst New Haven CT USA 06510 st, New Haven, CT 06510 USA
Titolo Testata:
BLOOD
fascicolo: 8, volume: 98, anno: 2001,
pagine: 2364 - 2371
SICI:
0006-4971(20011015)98:8<2364:ISKACA>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL ANTIGEN RECEPTOR; THYMOCYTE DEVELOPMENT; PEPTIDE LIGANDS; TUMOR-CELLS; PROTEIN; ACTIVATION; TCR; LCK; ANTAGONIST; SUFFICIENT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Geiger, TL St Jude Childrens Hosp, Dept Pathol, 332 N Lauderdale St,DT-4047E, Memphis, TN 38105 USA St Jude Childrens Hosp 332 N Lauderdale St,DT-4047E Memphis TN USA 38105
Citazione:
T.L. Geiger et al., "Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes", BLOOD, 98(8), 2001, pp. 2364-2371

Abstract

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 ligandrecognition 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) zeta 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 zeta signaling domain willenhance receptor function. The present study compares signaling characteristics of 9 single-chain receptors consisting of the H-2K(b) extracellular and transmembrane domains and various combinations of T cell signal transduction domains. Signal transduction regions studied include the TCR zeta 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 associationmay be predicted from the known functions of receptor constituents. The combination of zeta to gether with coreceptor and costimulatory function in asingle receptor maximizes chimeric receptor sensitivity and potency. Combining zeta 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. (C) 2001 by The American Society of Hematology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 07:56:27