Abstract

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that are believed to inhibit immune responses in the contexts of cancer and organ transplantation, in association with regulatory T cells (Treg). However, the way in which MDSC cooperate with Treg remains elusive. In this study, we used DNA microarrays to analyze gene expression in blood-derived MDSC from rat recipients of kidney allografts. We found CCL5 (Rantes), a chemotactic C-C motif 5 chemokine, to be strongly downregulated after treatment with a tolerizing regimen. The amount of CCL5 protein was also lower in the plasma of tolerant recipients, whereas intragraft CCL5 was unchanged. Because CCL5 is chemotactic for Treg, we hypothesized that a gradient of CCL5 between the graft and peripheral blood might contribute to the intragraft localization of Treg in tolerant animals. To test this hypothesis, we treated tolerant rat recipients of kidney allografts with recombinant rat CCL5 to restore normal plasma concentrations. This led to a strong reduction in intragraft Treg monitored by immunohistofluorescence and by quantitative real-time PCR measurement of Foxp3 mRNA. Ultimately, this treatment led to an increase in serum creatinine concentrations and to kidney graft rejection after about a month. The kidney function of syngeneic grafts was not affected by a similar administration of CCL5. These data highlight the contribution of MDSC to the establishment of a graft-to-periphery CCL5 gradient in tolerant kidney allograft recipients, which controls recruitment of Treg to the graft where they likely contribute to maintaining tolerance.

Links

Publisher Full Text

Authors

Dilek N, Poirier N, Usal C, Martinet B, Blancho G, Vanhove B

Institution

INSERM, Unité Mixte de Recherche en Santé 1064, Nantes F-44093, France;

Source

Journal of immunology (Baltimore, Md. : 1950) 188:9 2012 May 1 pg 4209-16

MeSH

Animals
Cell Line
Chemokine CCL5
Forkhead Transcription Factors
Gene Expression Profiling
Gene Expression Regulation
Kidney
Kidney Transplantation
Male
Mice
Myeloid Cells
Oligonucleotide Array Sequence Analysis
RNA, Messenger
Rats
Rats, Inbred Lew
T-Lymphocytes, Regulatory
Transplantation Tolerance
Transplantation, Homologous
Transplants

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22450806