Phenotypic and functional differences between wild-type and CCR2-/- dendritic cells: implications for islet transplantation.
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.


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.
Fiorina
Paolo
P
Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jurewicz
Mollie
M
Vergani
Andrea
A
Augello
Andrea
A
Paez
Jesus
J
Ricchiuti
Vincent
V
Tchipachvili
Vaja
V
Sayegh
Mohamed H
MH
Abdi
Reza
R
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D015847:Interleukin-4 / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
C515335:Ccr2 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D054390:Receptors, CCR2; D015847:Interleukin-4