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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Clin+Exp+Immunol
2015 ; 182
(2
): 220-9
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Messenger RNA encoding constitutively active Toll-like receptor 4 enhances
effector functions of human T cells
#MMPMID26212048
Pato A
; Eisenberg G
; Machlenkin A
; Margalit A
; Cafri G
; Frankenburg S
; Merims S
; Peretz T
; Lotem M
; Gross G
Clin Exp Immunol
2015[Nov]; 182
(2
): 220-9
PMID26212048
show ga
Adoptive T cell therapy of cancer employs a large number of ex-vivo-propagated T
cells which recognize their targets either by virtue of their endogenous T cell
receptor (TCR) or via genetic reprogramming. However, both cell-extrinsic and
intrinsic mechanisms often diminish the in-vivo potency of these therapeutic T
cells, limiting their clinical efficacy and broader use. Direct activation of
human T cells by Toll-like receptor (TLR) ligands induces T cell survival and
proliferation, boosts the production of proinflammatory cytokines and augments
resistance to regulatory T cell (Treg) suppression. Removal of the TLR
ligand-binding region results in constitutive signalling triggered by the
remaining cytosolic Toll/interleukin-1 receptor (TIR) domain. The use of such TIR
domains therefore offers an ideal means for equipping anti-tumour T cells with
the arsenal of functional attributes required for improving current clinical
protocols. Here we show that constitutively active (ca)TLR-4 can be expressed
efficiently in human T cells using mRNA electroporation. The mere expression of
caTLR-4 mRNA in polyclonal CD8 and CD4 T cells induced the production of
interferon (IFN)-?, triggered the surface expression of CD25, CD69 and 4-1BB and
up-regulated a panel of cytokines and chemokines. In tumour-infiltrating
lymphocytes prepared from melanoma patients, caTLR-4 induced robust IFN-?
secretion in all samples tested. Furthermore, caTLR-4 enhanced the anti-melanoma
cytolytic activity of tumour-infiltrating lymphocytes and augmented the secretion
of IFN-?, tumour necrosis factor (TNF)-? and granulocyte-macrophage
colony-stimulating factor (GM-CSF) for at least 4 days post-transfection. Our
results demonstrate that caTLR-4 is capable of exerting multiple T cell-enhancing
effects and can potentially be used as a genetic adjuvant in adoptive cell
therapy.