Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction.
Thymic-derived CD25+ CD4+ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we evaluated the ability of dendritic cells (DCs) to expand alloantigen-specific Tregs in the mixed leukocyte reaction (MLR) that develops from polyclonal populations of T cells. The allogeneic DCs, when supplemented with IL-2 in the cultures, were much more effective than bulk spleen cells in expanding the numbers of Tregs. Likewise, DCs and not spleen cells were effective in sustaining expression of the transcription factor Foxp3 in Tregs, but neither IL-2 nor CD80/86 was required for this effect in the cultures. On a per-cell basis, the DC-expanded, but not unexpanded, Tregs were more potent suppressors of a fresh MLR by CD25- CD4+ T cells. Suppression was 3- to 10-fold more active for MLRs induced by the original alloantigens than for third-party stimulators. When DC-expanded Tregs were introduced into sublethally irradiated hosts, the T cells suppressed graft-versus-host-disease induced by CD25- CD4+ T cells. Again, suppression was more active against the same mouse strain that provided the DCs to expand the Tregs. Therefore, alloantigen-selected Tregs are more effective suppressors of responses to major transplantation antigens, and these Tregs can be expanded from a polyclonal repertoire by DCs.
Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York, NY 10021, USA.
Sayuri
S
Yamazaki
Munjal
M
Patel
Alice
A
Harper
Anthony
A
Bonito
Hidehiro
H
Fukuyama
Maggi
M
Pack
Kristin V
KV
Tarbell
Mia
M
Talmor
Jeffrey V
JV
Ravetch
Kayo
K
Inaba
Ralph M
RM
Steinman
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006086:Graft vs Host Disease / Q000628:therapy; D007165:Immunosuppression Therapy / Q000379:methods; D007376:Interleukin-2 / Q000494:pharmacology; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D007519:Isoantigens; D015375:Receptors, Interleukin-2