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. 2019 Mar 15;202(6):1735-1746.
doi: 10.4049/jimmunol.1801004. Epub 2019 Feb 6.

"VSports在线直播" Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells

Susann Albert  1   2 , Stefanie Koristka  1 , Alexander Gerbaulet  3 , Marc Cartellieri  4 , Claudia Arndt  1 , Anja Feldmann  1 , Nicole Berndt  1   5 , Liliana R Loureiro  1 , Malte von Bonin  5   6 , Gerhard Ehninger  2   6   7 , Anne Eugster  8 , Ezio Bonifacio  8 , Martin Bornhäuser  2   5   6   7 , Michael P Bachmann  9   2   5   7 , Armin Ehninger  6   10
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Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells

Susann Albert et al. J Immunol. .

Abstract

Long-term survival of adoptively transferred chimeric Ag receptor (CAR) T cells is often limited. Transplantation of hematopoietic stem cells (HSCs) transduced to express CARs could help to overcome this problem as CAR-armed HSCs can continuously deliver CAR+ multicell lineages (e. g. , T cells, NK cells) VSports手机版. In dependence on the CAR construct, a variable extent of tonic signaling in CAR T cells was reported; thus, effects of CAR-mediated tonic signaling on the hematopoiesis of CAR-armed HSCs is unclear. To assess the effects of tonic signaling, two CAR constructs were established and analyzed 1) a signaling CAR inducing a solid Ag-independent tonic signaling termed CAR-28/ζ and 2) a nonstimulating control CAR construct lacking intracellular signaling domains termed CAR-Stop. Bone marrow cells from immunocompetent mice were isolated, purified for HSC-containing Lin-cKit+ cells or the Lin-cKit+ Sca-1+ subpopulation (Lin-Sca-1+cKit+), and transduced with both CAR constructs. Subsequently, modified bone marrow cells were transferred into irradiated mice, in which they successfully engrafted and differentiated into hematopoietic progenitors. HSCs expressing the CAR-Stop sustained normal hematopoiesis. In contrast, expression of the CAR-28/ζ led to elimination of mature CAR+ T and B cells, suggesting that the CAR-mediated tonic signaling mimics autorecognition via the newly recombined immune receptors in the developing lymphocytes. .

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