Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance.
BACKGROUND
Harnessing naturally arising CD4+ CD25+ regulatory T cells (Tregs) for potential adoptive cell therapy is hampered by their innate autoreactivity and their limited number.


METHODS
CD4+ CD25+ Tregs were purified from peripheral blood of human leukocyte antigen (HLA) DR1*0101+ A2- individuals, and stimulated with autologous monocyte-derived dendritic cells (DCs).


RESULTS
Here we show that CD4+ CD25+ Tregs specific for an HLA A2 (103-120) peptide can be selected from the peripheral blood CD4+ CD25+ T cell population of a healthy individual and detected using a tetramer comprised of HLA DRB1*0101 and the A2 peptide. The selected cells can be expanded substantially (i.e., a 1600-fold increase over a two-week period) by T-cell receptor (TCR) stimulation and high-doses of interleukin-2 (IL-2). The CD4+ CD25+Tregs with indirect allospecificity for the A2 peptide showed more potent antigen-specific suppression than polyclonal CD4+ CD25+ Tregs.


CONCLUSIONS
These data may pave the way for clinical studies using CD4+ CD25+ Tregs with indirect allospecificity as therapeutic reagents for the induction of donor-specific transplantation tolerance.
Jiang
Shuiping
S
Department of Nephrology and Transplantation, King's College London, Guy's Hospital, London, United Kingdom. shuiping.jiang@kcl.ac.uk
Tsang
Julia
J
Game
David S
DS
Stevenson
Saskia
S
Lombardi
Giovanna
G
Lechler
Robert I
RI
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D018929:Cell Culture Techniques; D003713:Dendritic Cells / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D059811:HLA-DRB1 Chains; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D014019:Tissue Donors; D023001:Transplantation Tolerance
D015704:CD4 Antigens; C517366:HLA A2 (103-120) peptide, human; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D059811:HLA-DRB1 Chains; C487961:HLA-DRB1*01:01 antigen; D053645:Interleukin-2 Receptor alpha Subunit; D010446:Peptide Fragments