Maturation-resistant dendritic cells induce hyporesponsiveness in alloreactive CD45RA+ and CD45RO+ T-cell populations.
Dendritic cells (DCs) play a crucial role in the induction of antigen-specific immunity and tolerance. Considering in vivo application of DCs prior to human organ transplantation, a protocol to develop tolerogenic DCs that not only induce unresponsiveness in naive (CD45RA+) T cells, but also in alloreactive memory (CD45RO+) T cells is required. The present study shows that dexamethasone (Dex) alters the differentiation of human monocyte-derived DCs. DexDCs cocultured with allogeneic CD4+ T cells induced low proliferating and low IFNgamma producing T cells. This is caused by lack of both costimulation via CD28 and hampered production of a soluble factor, as well as additional active suppression via B7-H1 and IL-10. T cells primed by DexDCs demonstrated hyporesponsiveness upon restimulation with mature DCs seemingly via the induction of anergy, since these cells showed no enhanced apoptosis and only a limited suppressive capacity. Interestingly, not only cocultures of allogeneic CD45RA+, but also of CD45RO+ T cells with DexDCs rendered T-cell populations hyporesponsive to restimulation with mature DCs. The finding that also alloreactive memory T cells can be regulated supports the rationale of cell-based therapies to obtain allograft-specific tolerance in transplant recipients.
Woltman
A M
AM
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
van der Kooij
S W
SW
de Fijter
J W
JW
van Kooten
C
C
D015703:Antigens, CD / Q000276:immunology; D060890:B7-H1 Antigen; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D007519:Isoantigens; D016753:Interleukin-10; D003907:Dexamethasone; D017493:Leukocyte Common Antigens