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J Immunol. 2019 Feb 6. pii: ji1801004. doi: 10.4049/jimmunol.1801004. [Epub ahead of print]

Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells.

Author information

1
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01328 Dresden, Germany.
2
University Cancer Center (UCC), Tumor Immunology, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.
3
Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.
4
Cellex Patient Treatment GmbH, 01307 Dresden, Germany.
5
German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
6
Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.
7
National Center for Tumor Diseases (NCT), partner site Dresden, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.
8
Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, 01307 Dresden, Germany; and.
9
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01328 Dresden, Germany; m.bachmann@hzdr.de.
10
GEMoaB Monoclonals GmbH, 01307 Dresden, Germany.

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). 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.

PMID:
30728213
DOI:
10.4049/jimmunol.1801004

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