Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3.
Therapies based on enhancing the numbers and/or function of T regulatory cells (Tregs) represent one of the most promising approaches to restoring tolerance in many immune-mediated diseases. Several groups have investigated whether human Tregs suitable for cellular therapy can be obtained by in vitro expansion, in vitro conversion of conventional T cells into Tregs, or gene transfer of the FOXP3 transcription factor. To date, however, none of these approaches has resulted in a homogeneous and stable population of cells that is as potently suppressive as ex vivo Tregs. We developed a lentivirus-based strategy to ectopically express high levels of FOXP3 that do not fluctuate with the state of T-cell activation. This method consistently results in the development of suppressive cells that are as potent as Tregs and can be propagated as a homogeneous population. Moreover, using this system, both naïve and memory CD4(+) T cells can be efficiently converted into Tregs. To date, this is the most efficient and reliable protocol for generating large numbers of suppressive CD4(+) Tregs, which can be used for further biological study and developed for antigen-specific cellular therapy applications.
Allan
Sarah E
SE
Department of Surgery, University of British Columbia, Vancouver, Canada.
Alstad
Alicia N
AN
Merindol
Natacha
N
Crellin
Natasha K
NK
Amendola
Mario
M
Bacchetta
Rosa
R
Naldini
Luigi
L
Roncarolo
Maria Grazia
MG
Soudeyns
Hugo
H
Levings
Megan K
MK
D016475:3T3 Cells; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D019169:Jurkat Cells; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020079:Terminal Repeat Sequences
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors