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001-es BibID:	BIBFORM057538
035-os BibID:	(scopus)84910122146 (wos)000345023400059
Első szerző:	Govers, Coen
Cím:	TCRs genetically linked to CD28 and CD3[epszilon] do not mispair with endogenous TCR chains and mediate enhanced t cell persistence and anti-melanoma activity / Coen Govers, Zsolt Sebestyén, János Roszik, Mandy van Brakel, Cor Berrevoets, Árpád Szöőr, Konstantina Panoutsopoulou, Marieke Broertjes, Tan Van, György Vereb, János Szöllősi, Reno Debets
Dátum:	2014
ISSN:	0022-1767 1550-6606
Megjegyzések:	Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by adequate T cell costimulation. In this article, we report the identification and characterization of a novel two-chain TCR linked to CD28 and CD3[epszilon] (i.e., TCR:28[epszilon]). This modified TCR demonstrates enhanced binding of peptide-MHC and mediates enhanced T cell function following stimulation with peptide compared with wild-type TCR. Surface expression of TCR:28[epszilon] depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3[epszilon], with IL-2 production showing dependency on CD28:LCK binding. TCR:28[epszilon], but not wild-type TCR, induces detectable immune synapses in primary human T cells, and such immune synapses show significantly enhanced accumulation of TCR transgenes and markers of early TCR signaling, such as phosphorylated LCK and ERK. Importantly, TCR:28[epszilon] does not show signs of off-target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28[epszilon] in immune-competent mice, we observed a drastic increase in T cell survival, which was accompanied by regression of large melanomas with limited recurrence. Our data argue that TCR transgenes that contain CD28, and, thereby, may provide T cell costimulation in an immune-suppressive environment, represent candidate receptors to treat patients with tumors.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk TCR T Cell
Megjelenés:	Journal Of Immunology. - 193 : 10 (2014), p. 5315-5326. -
További szerzők:	Sebestyén Zsolt Roszik János (1979-) (biofizikus) van Brakel, Mandy Berrevoets, Cor Szöőr Árpád (1984-) (orvos) Panoutsopoulou, Konstantina Broertjes, Marieke Van, Tan Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus) Debets, Reno
Pályázati támogatás:	TÁMOP-4.2.1/B-09/1/KONV-2010-0007 TÁMOP TÁMOP-4.2.2/B-10/1/2010-0024 TÁMOP TÁMOP-4.2.2/A-11/1/KONV-20120025 TÁMOP OTKA-NK101337 OTKA
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