Provision of antifungal immunity and concomitant alloantigen tolerization by conditioned dendritic cells in experimental hematopoietic transplantation.
FoxP3(+) regulatory T (Treg) cells are important mediators of peripheral tolerance, and deficiency of this population is associated with autoimmune inflammation and onset of acute lethal graft-vs.-host disease in transplantation. Type I IFN-producing plasmacytoid dendritic cells (pDC) are implicated in the induction and maintenance of tolerance and contribute to engraftment facilitation and prevention of graft-vs.-host disease after allogeneic hematopoietic stem cells transplantation (HSCT). Because host DC function is impaired during the immediate period post-transplant, the administration of donor DC may be useful for the educational program of recovering T cells. Distinct DC subsets could be derived from bone marrow (murine) or peripheral CD14(+) cell (human) cultures in the presence of either GM-CSF/IL-4 (myeloid DC) or FLT3-ligand (mainly pDC). The ability of either DC subset to induce Th1/Treg cell priming against Aspergillus fumigatus as well as the relative contribution of murine DC subsets to antifungal priming upon adoptive transfer in hematopoietic transplanted mice with aspergillosis is not known. We found specialization and complementarity in priming and tolerization by the different DC subsets, with FL-DC fulfilling the requirement for (i) Th1/Treg antifungal priming; ii) tolerization toward alloantigens and (iii) diversion from alloantigen-specific to antigen-specific T cell responses in the presence of donor T lymphocytes. Interestingly, thymosin alpha1 (Talpha1), known to modulate human pDC functions trough TLR9, affects mobilization and tolerization of pDC by activating the indoleamine 2,3-dioxygenase-dependent pathway, and this resulted in Treg development and tolerization. Thus, transplantation tolerance and concomitant pathogen clearance could be achieved through the therapeutic induction of antigen-specific Treg cells via instructive immunotherapy with pathogen- or TLR-conditioned donor DC.
Montagnoli
Claudia
C
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Perruccio
Katia
K
Bozza
Silvia
S
Bonifazi
Pierluigi
P
Zelante
Teresa
T
De Luca
Antonella
A
Moretti
Silvia
S
D'Angelo
Carmen
C
Bistoni
Francesco
F
Martelli
Massimo
M
Aversa
Franco
F
Velardi
Andrea
A
Romani
Luigina
L
D000818:Animals; D001228:Aspergillosis / Q000209:etiology / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology