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Published online before print August 7, 2007

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(Journal of Leukocyte Biology. 2007;82:1053-1061.)
© 2007 by Society for Leukocyte Biology

Blockade of chronic graft-versus-host disease by alloantigen-induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells in nonlymphopenic hosts

King’s College London, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom

² Correspondence: Department of Asthma, Allergy, and Respiratory Science, King’s College London, 5th Floor Thomas Guy House, Guy’s Hospital Campus, London SE1 9RT, UK. E-mail: alistair.noble{at}kcl.ac.uk

ABSTRACT

CD4⁺CD25⁺ regulatory T cells (Tregs) are well known to suppress immunopathology induced in lymphopenic animals following T cell reconstitution, including acute graft-versus-host disease (GVHD) post-bone marrow transplantation. The regulatory potential of this subset in nonlymphopenic hosts and in chronic, Th2-mediated GVHD is less clear. We have generated alloantigen-specific cells from CD4⁺CD25⁺ populations stimulated with MHC-disparate dendritic cells and found them to express a stable Treg forkhead box p3⁺ phenotype with enhanced suppressive activity mediated by cell contact. When transferred into nonlymphopenic F1 hosts, nonspecific Tregs proliferated as rapidly as CD4⁺CD25^– cells but displayed distinct growth kinetics in vitro. Tregs, expanded in response to alloantigen in vitro, displayed greatly enhanced suppressive activity, which was partially antigen-specific. They were effective inhibitors of chronic GVHD, blocking donor cell engraftment, splenomegaly, autoantibody production, and glomerulonephritis. CD25⁺ and CD25^– cells were equally susceptible to inhibition by immunosuppressive drugs targeting TCR signaling and rapamycin, but Tregs were resistant to inhibition by dexamethasone. The data indicate that alloantigen-driven expansion, rather than homeostatic proliferation, is key to the effectiveness of CD4⁺CD25⁺ Tregs in GVHD and suggest that cellular therapy with alloantigen-induced Tregs in combination with glucocorticoid treatment would be effective in prevention of chronic GVHD after immune reconstitution.

Key Words: alloreactivity • suppression • dexamethasone

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