title: Human CD45RA(-) FoxP3(hi) Memory-Type Regulatory T Cells Show Distinct TCR Repertoires With Conventional T Cells and Play an Important Role in Controlling Early Immune Activation.
abstract: Adoptive immunotherapy with regulatory T cells (Treg) is a new option to promote immune tolerance following solid organ transplantation (SOT). However, Treg from elderly patients awaiting transplantation are dominated by the CD45RA(-) CD62L(+) central memory type Treg subset (TregCM), and the yield of well-characterized and stable naïve Treg (TregN) is low. It is, therefore, important to determine whether these TregCM are derived from the thymus and express high stability, suppressive capacity and a broad antigen repertoire like TregN. In this study, we showed that TregCM use a different T cell receptor (TCR) repertoire from conventional T cells (Tconv), using next-generation sequencing of all 24 Vβ families, with an average depth of 534 677 sequences. This showed almost no contamination with induced Treg. Furthermore, TregCM showed enhanced suppressive activity on Tconv at early checkpoints of immune activation controlling activation markers expression and cytokine secretion, but comparable inhibition of proliferation. Following in vitro expansion under mTOR inhibition, TregCM expanded equally as well as TregN without losing their function. Despite relatively limited TCR repertoire, TregCM also showed specific alloresponse, although slightly reduced compared to TregN. These results support the therapeutic usefulness of manufacturing Treg products from CD45RA(-) CD62L(+) Treg-enriched starting material to be applied for adoptive Treg therapy.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Lei
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|International Max Planck Research School for Computational Biology and Scientific Computing, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Kuchenbecker
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Streitz
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Vogt
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Department of Pediatric Pulmonology and Immunology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Landwehr-Kenzel
authors.affiliation: Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.|Experimental and Clinical Research Center (ECRC), MDC and Charité University Medicine, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Millward
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Juelke
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Department of Nephrology and Intensive Care, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Babel
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Goodman Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel.|Institute for Theoretical Biology, Humboldt University, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Neumann
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Department of Nephrology and Intensive Care, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Reinke
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.|Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: H-D
authors.initials: HD
authors.lastname: Volk
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D016030:Kidney Transplantation; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D015415:Biomarkers; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell; D017493:Leukocyte Common Antigens
keywords: Immune regulation; T cell biology; tolerance