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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2220-2226.
Prepublished online as a Blood First Edition Paper on November 16, 2004; DOI 10.1182/blood-2004-05-2044.


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TRANSPLANTATION

Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD

Joerg Ermann, Petra Hoffmann, Matthias Edinger, Suparna Dutt, Francis G. Blankenberg, John P. Higgins, Robert S. Negrin, C. Garrison Fathman, and Samuel Strober

From the Division of Immunology and Rheumatology and the Division of Bone Marrow Transplantation, the Department of Medicine, the Department of Radiology, and the Department of Pathology, Stanford University School of Medicine, Stanford, CA; the Department of Medicine, University of Tennessee, Memphis, TN; and the Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.

CD4+CD25+ regulatory T (Treg) cells are potent modulators of alloimmune responses. In murine models of allogeneic bone marrow transplantation, adoptive transfer of donor CD4+CD25+ Treg cells protects recipient mice from lethal acute graft-versus-host disease (aGVHD) induced by donor CD4+CD25- T cells. Here we examined the differential effect of CD62L+ and CD62L- subsets of CD4+CD25+ Treg cells on aGVHD-related mortality. Both subpopulations showed the characteristic features of CD4+CD25+ Treg cells in vitro and did not induce aGVHD in vivo. However, in cotransfer with donor CD4+CD25- T cells, only the CD62L+ subset of CD4+CD25+ Treg cells prevented severe tissue damage to the colon and protected recipients from lethal aGVHD. Early after transplantation, a higher number of donor-type Treg cells accumulated in host mesenteric lymph node (LN) and spleen when CD4+CD25+CD62L+ Treg cells were transferred compared with the CD62L- subset. Subsequently, CD4+CD25+CD62L+ Treg cells showed a significantly higher capacity than their CD62L- counterpart to inhibit the expansion of donor CD4+CD25- T cells. The ability of Treg cells to efficiently enter the priming sites of pathogenic allo-reactive T cells appears to be a prerequisite for their protective function in aGVHD.


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