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Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockade^l

Bert Verbinnen^*, An D. Billiau, Jan Vermeiren^*, Georgina Galicia^*, Dominique M. A. Bullens^*,, Louis Boon^¶, Pascal Cadot^*, Greet Hens^*, Christiane Dewolf-Peeters, Stefaan W. Van Gool^*, and Jan L. Ceuppens^2,*

^* Division of Clinical Immunology, Experimental Transplantation, Pediatrics, and Morphology and Molecular Pathology, University Hospital, Catholic University of Leuven, Leuven, Belgium; and ^¶ Bioceros, Utrecht, The Netherlands

Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F₁ offspring (C57BL/6 x C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25⁺ cell-depleted splenocyte transfer, showing that CD25⁺ natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6–30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3⁺ cells among donor CD4⁺ cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

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¹ This work was supported by a research grant from the Research Council of the Catholic University of Leuven (OT 06-67), by research grants from the Fund for Scientific Research-Flanders (G.0509.06 and G.0255.05) and by a grant from the Institute for the Promotion of Innovation through Science and Technology in Flanders. B.V. is a recipient of a fellowship from Institute for the Promotion of Innovation through Science and Technology in Flanders. S.W.V.G. is a senior clinical investigator of the Fund for Scientific Research-Flanders. A.D.B. and D.M.A.B. are recipients of a postdoctoral fellowship from the Fund for Scientific Research.

² Address correspondence and reprint requests to Dr. Jan Ceuppens, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail address: jan.ceuppens{at}uz.kuleuven.be

³ Abbreviations used in this paper: Treg, regulatory T cell; nTreg, natural Treg; GVHR, graft-vs-host reaction; GVHD, graft-vs-host disease; WBC, white blood cell.