PMID- 30619313
OWN - NLM
STAT- MEDLINE
DCOM- 20191025
LR  - 20211204
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - Selective Effects of mTOR Inhibitor Sirolimus on Naive and CMV-Specific T Cells 
      Extending Its Applicable Range Beyond Immunosuppression.
PG  - 2953
LID - 10.3389/fimmu.2018.02953 [doi]
LID - 2953
AB  - Cytomegalovirus (CMV) infection/reactivation remains among the most important 
      complications of immunosuppression after transplantation. However, recent 
      clinical observations indicate that mammalian target of rapamycin (mTOR) 
      inhibition with sirolimus may improve the outcome of CMV complications. 
      Underlying mechanisms of this observation, particularly the effect of sirolimus 
      on naive- and CMV-specific cytotoxic CD8(+) T-cell (CMV-CTL) functionality is 
      still undiscovered. Here, the influence of sirolimus on naive and memory CMV-CTLs 
      was determined by CD3/CD28 crosslinking and alloreactivity assays. After 
      stimulating CMV-CTL with HLA-A(*)02:01-restricted CMVpp65-peptide loaded 
      artificial antigen-presenting cells (aAPCs), we measured the effect of sirolimus 
      on T-cell proliferation, phenotype, and functionality. Sirolimus significantly 
      improved CMV-specific effector memory T-cell function and negatively influenced 
      naive T cells. This unique mechanism of action was further characterized by 
      increased secretion of interferon-gamma (IFN-gamma), granzyme B (GzB) and enhanced 
      target-cell-dependent cytotoxic capacity of activated CMV-CTLs. 
      Next-generation-sequencing (NGS) was applied to monitor T-cell receptor 
      (TCR)-repertoire dynamics and to verify, that the increased functionality was not 
      related to sirolimus-resistant CTL-clones. Instead, modulation of environmental 
      cues during CMV-CTL development via IL-2 receptor (IL-2R)-driven signal 
      transducer and activator of transcription-5 (STAT-5) signaling under mTOR 
      inhibition allowed fine-tuning of T-cell programming for enhanced antiviral 
      response with stable TCR-repertoire dynamics. We show for the first time that 
      sirolimus acts selectively on human naive and memory T cells and improves 
      CMV-specific T-cell function via modulation of the environmental milieu. The data 
      emphasize the importance to extend immune monitoring including cytokine levels 
      and T-cell functionality which will help to identify patients who may benefit 
      from individually tailored immunosuppression.
FAU - Bak, Szilvia
AU  - Bak S
AD  - Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.
FAU - Tischer, Sabine
AU  - Tischer S
AD  - Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.
FAU - Dragon, Anna
AU  - Dragon A
AD  - Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.
FAU - Ravens, Sarina
AU  - Ravens S
AD  - Hannover Medical School, Institute of Immunology, Hannover, Germany.
FAU - Pape, Lars
AU  - Pape L
AD  - Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany.
FAU - Koenecke, Christian
AU  - Koenecke C
AD  - Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, 
      Hannover Medical School, Hannover, Germany.
FAU - Oelke, Mathias
AU  - Oelke M
AD  - Department of Pathology, John Hopkins School of Medicine, Baltimore, MD, United 
      States.
AD  - NexImmune Inc., Gaithersburg, MD, United States.
FAU - Blasczyk, Rainer
AU  - Blasczyk R
AD  - Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.
FAU - Maecker-Kolhoff, Britta
AU  - Maecker-Kolhoff B
AD  - Department of Pediatric Hematology and Oncology, Hannover Medical School, 
      Hannover, Germany.
FAU - Eiz-Vesper, Britta
AU  - Eiz-Vesper B
AD  - Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181217
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Cytokines)
RN  - 0 (Receptors, Interleukin-2)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adolescent
MH  - Child
MH  - Cytokines/blood/immunology/metabolism
MH  - Cytomegalovirus/*immunology
MH  - Cytomegalovirus Infections/blood/immunology/*prevention & control/virology
MH  - Female
MH  - Graft Rejection/immunology/prevention & control
MH  - Hematopoietic Stem Cell Transplantation/adverse effects
MH  - Humans
MH  - Immunosuppression Therapy/*methods
MH  - Kidney Transplantation/adverse effects
MH  - Male
MH  - Patient Selection
MH  - Receptors, Interleukin-2/blood/immunology
MH  - Sirolimus/*administration & dosage
MH  - T-Lymphocytes, Cytotoxic/*drug effects/immunology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/immunology
MH  - Transplantation, Homologous/adverse effects
MH  - Virus Activation/drug effects/immunology
PMC - PMC6304429
OTO - NOTNLM
OT  - HCMV
OT  - antiviral T cells
OT  - mTOR inhibitor
OT  - personalized immunosuppression
OT  - sirolimus
OT  - transplantation
EDAT- 2019/01/09 06:00
MHDA- 2019/10/28 06:00
PMCR- 2018/01/01
CRDT- 2019/01/09 06:00
PHST- 2018/08/13 00:00 [received]
PHST- 2018/11/30 00:00 [accepted]
PHST- 2019/01/09 06:00 [entrez]
PHST- 2019/01/09 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.02953 [doi]
PST - epublish
SO  - Front Immunol. 2018 Dec 17;9:2953. doi: 10.3389/fimmu.2018.02953. eCollection 
      2018.