Rovira, Jordi and Sabet-Baktach, Manije and Eggenhofer, Elke and Lantow, Margareta and Koehl, Gudrun E. and Schlitt, Hans J. and Campistol, Josep M. and Geissler, Edward K. and Kroemer, Alexander (2013) A Color-Coded Reporter Model to Study the Effect of Immunosuppressants on CD8(+) T-Cell Memory in Antitumor and Alloimmune Responses. TRANSPLANTATION, 95 (1). pp. 54-62. ISSN 0041-1337,
Full text not available from this repository. (Request a copy)Abstract
Background. Mammalian target of rapamycin (mTOR) inhibitors possess anticancer properties potentially useful in reducing posttransplantation malignancy. Besides controlling tumor-sensitive proliferative and angiogenic effects, mTOR influences transcription factors T-bet and Eomesodermin (Eomes) in CD8(+) cytotoxic T cells (Tc), which are key in rejecting tumors, and allografts. Methods. To study the role of mTOR in tumor and transplant immunity in an antigen-specific way, we used T-cell receptor transgenic B6.OTI recipients, B6.OVA.TG donors, and OVA-B16F10 melanoma cells. For tracking color-coded OTI-Tc cells associated with antitumor and alloimmunity in vivo, CD8-OTI transgenic reporter mice were created by crossbreeding DsRed-expressing B6.Nagy mice with B6.OTI mice. Results. The role of mTOR in regulating the differentiation and function of alloreactive Tc cells in vitro was explored by stimulating OTI-Tc cells with ovalbumin-transgenic antigen-presenting cells in the presence of rapamycin or tacrolimus. Rapamycin, but not tacrolimus, induced a pro-antitumor phenotypic shift from CD62L(-)CD44(+) effector memory Tc cells to CD62L(+)CD44(+) central memory Tc cells, which featured up-regulated levels of T-bet and Eomes and preserved levels of interferon-gamma and perforin. For future investigations, an in vivo model was established whereby DsRed(+)OTI-Tc cells adoptively transferred into B6 mice bearing either a ovalbumin-transgenic mouse skin transplant or OVA-B16F10 tumor could be traced by fluorescence-activated cell sorting analysis as effector or memory Tc cells in transplant and tumor tissues. Conclusion. mTOR, but not calcineurin, inhibition spares antitumoral memory Tc cells by distinctively regulating T-bet and Eomes. This finding is now testable in a new tumor transplant model, which incorporates DsRed(+)OTI-Tc cell tracing, opening the way to study the differential effects of immunosuppressants in posttransplantation malignancy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RENAL-TRANSPLANT RECIPIENTS; ENDOTHELIAL GROWTH-FACTOR; ORGAN-TRANSPLANTATION; CUTTING EDGE; TRANSCRIPTION FACTOR; MTOR INHIBITION; CANCER; EXPRESSION; DIFFERENTIATION; PROGRESSION; mTOR; CD8(+) T cells; Transplantation; Antitumoral immunity |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Apr 2020 10:12 |
| Last Modified: | 28 Apr 2020 10:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17287 |
Actions (login required)
 |
View Item |
