TY - JOUR
T1 - Phenotypic and functional differences between wild-type and CCR2 -/- dendritic cells
T2 - Implications for islet transplantation
AU - Fiorina, Paolo
AU - Jurewicz, Mollie
AU - Vergani, Andrea
AU - Augello, Andrea
AU - Paez, Jesus
AU - Ricchiuti, Vincent
AU - Tchipachvili, Vaja
AU - Sayegh, Mohamed H.
AU - Abdi, Reza
PY - 2008/4
Y1 - 2008/4
N2 - BACKGROUND. Trafficking of dendritic cells (DC), the primary regulators of alloimmune responses, is controlled by chemokines. Here, we provide evidence that lack of CCR2 could lead to the generation of functionally and phenotypically different DC, which in part could explain the benefits observed in transplanting islets in CCR2 recipients. METHODS AND RESULTS. We show that, in contrast to the in vitro DC maturation model, in vivo DC maturation is accompanied by an increase in the expression of CCR2. Compared with wild-type (WT), DC generated in vitro from CCR2 mice, and DC extracted from CCR2 naïve mice or from CCR2 recipients of islet allografts, display lesser allostimulatory capacity. Compared with WT DC, CCR2 DC produce more IL-4 and induce more IL-4-producing T cells. CCR2 DC also promote the generation of regulatory T cells that more efficiently suppress T cell proliferative responses by mixed leukocyte reaction. Similarly, the percentage of CD4CD25FoxP3 cells were found to be higher in CCR2 recipients of islet allografts than in WT recipients. CONCLUSIONS. In summary, lack of CCR2 interferes with the allostimulatory capacity of DC and promotes the generation of regulatory T cells. This is the first demonstration of a mechanistic link between targeting a specific chemokine pathway and the DC-regulatory T cell axis in alloimmunity.
AB - BACKGROUND. Trafficking of dendritic cells (DC), the primary regulators of alloimmune responses, is controlled by chemokines. Here, we provide evidence that lack of CCR2 could lead to the generation of functionally and phenotypically different DC, which in part could explain the benefits observed in transplanting islets in CCR2 recipients. METHODS AND RESULTS. We show that, in contrast to the in vitro DC maturation model, in vivo DC maturation is accompanied by an increase in the expression of CCR2. Compared with wild-type (WT), DC generated in vitro from CCR2 mice, and DC extracted from CCR2 naïve mice or from CCR2 recipients of islet allografts, display lesser allostimulatory capacity. Compared with WT DC, CCR2 DC produce more IL-4 and induce more IL-4-producing T cells. CCR2 DC also promote the generation of regulatory T cells that more efficiently suppress T cell proliferative responses by mixed leukocyte reaction. Similarly, the percentage of CD4CD25FoxP3 cells were found to be higher in CCR2 recipients of islet allografts than in WT recipients. CONCLUSIONS. In summary, lack of CCR2 interferes with the allostimulatory capacity of DC and promotes the generation of regulatory T cells. This is the first demonstration of a mechanistic link between targeting a specific chemokine pathway and the DC-regulatory T cell axis in alloimmunity.
KW - Chemokines
KW - Dendritic cells
KW - Islet transplantation
KW - Regulatory cells
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=42149172545&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42149172545&partnerID=8YFLogxK
U2 - 10.1097/TP.0b013e31816843a0
DO - 10.1097/TP.0b013e31816843a0
M3 - Article
C2 - 18408585
AN - SCOPUS:42149172545
VL - 85
SP - 1030
EP - 1038
JO - Transplantation
JF - Transplantation
SN - 0041-1337
IS - 7
ER -