Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion.
The immune tolerance to rat kidney allografts induced by a perioperative treatment with anti-CD28 Abs is associated with a severe unresponsiveness of peripheral blood cells to donor Ags. In this model, we identified an accumulation in the blood of CD3(-)class II(-)CD11b(+)CD80/86(+) plastic-adherent cells that additionally expressed CD172a as well as other myeloid markers. These cells were able to inhibit proliferation, but not activation, of effector T cells and to induce apoptosis in a contact-dependent manner. Their suppressive action was found to be under the control of inducible NO synthase, an enzyme also up-regulated in tolerated allografts. Based on these features, these cells can be defined as myeloid-derived suppressor cells (MDSC). Interestingly, CD4(+)CD25(high)FoxP3(+) regulatory T cells were insensitive in vitro to MDSC-mediated suppression. Although the adoptive transfer of MDSC failed to induce kidney allograft tolerance in recently transplanted recipients, the maintenance of tolerance after administration of anti-CD28 Abs was found to be dependent on the action of inducible NO synthase. These results suggest that increased numbers of MDSC can inhibit alloreactive T cell proliferation in vivo and that these cells may participate in the NO-dependent maintenance phase of tolerance.
Institut National de la Santé et de la Recherche Médicale, U643, Centre Hospitalier Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation, Université de Nantes, Faculté de Médecine, Nantes, France.
Anne-Sophie
AS
Dugast
Thomas
T
Haudebourg
Flora
F
Coulon
Michèle
M
Heslan
Fabienne
F
Haspot
Nicolas
N
Poirier
Romain
R
Vuillefroy de Silly
Claire
C
Usal
Helga
H
Smit
Bernard
B
Martinet
Pamela
P
Thebault
Karine
K
Renaudin
Bernard
B
Vanhove
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D039481:CD11b Antigen / Q000096:biosynthesis; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D007108:Immune Tolerance; D016130:Immunophenotyping; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D018448:Models, Immunological; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D039481:CD11b Antigen; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat