Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.
Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.
Kleinclauss
F
F
INSERM U645, 1 Bd A Fleming, Besançon F-25020, France.
Perruche
S
S
Masson
E
E
de Carvalho Bittencourt
M
M
Biichle
S
S
Remy-Martin
J-P
JP
Ferrand
C
C
Martin
M
M
Bittard
H
H
Chalopin
J-M
JM
Seilles
E
E
Tiberghien
P
P
Saas
P
P
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control; D007108:Immune Tolerance; D066298:In Vitro Techniques; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013154:Spleen / Q000166:cytology* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta