title: Host CD25+CD4+Foxp3+ regulatory T cells primed by anti-CD137 mAbs inhibit graft-versus-host disease.
abstract: CD25(+)CD4(+)Foxp3(+) regulatory T cells (Tregs) play a pivotal role in the maintenance of self-tolerance and regulation of immune responses. Previous studies have demonstrated that CD137 signals can promote proliferation and survival of Tregs in vitro. Here, we show that in vivo CD137-induced expansion of Tregs in naive mice was dependent upon IL-2 secreted by memory T cells. Tregs primed by anti-CD137 mAbs had a higher immunosuppressive capacity. Preconditioning with anti-CD137 mAbs significantly inhibited graft-versus-host disease (GVHD) in the C57BL/6 → (C57BL/6 × DBA/2) F1 acute GVHD model. In this disease model, a high proportion of host Tregs remained long-term in the recipient spleen, whereas donor hematopoietic cells replaced other host bone marrow-derived cells. Transient depletion of Tregs before transfer of donor cells completely abrogated the inhibitory effect of anti-CD137 mAbs on GVHD. In addition, adoptive transfer of anti-CD137-primed Tregs ameliorated GVHD. Our results demonstrate that it is possible to enhance the survival and/or the immunosuppressive activity of host Tregs in nonmyeloablative GVHD, and that 1 way of accomplishing this is through the prophylactic use of anti-CD137 mAbs in nonmyeloablative GVHD.
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, School of Medicine, University of Ulsan, Korea.
authors.forename: Juyang
authors.initials: J
authors.lastname: Kim
authors.forename: Wongyoung
authors.initials: W
authors.lastname: Kim
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sohye
authors.initials: S
authors.lastname: Park
authors.forename: Hyun-A
authors.initials: HA
authors.lastname: Kim
authors.forename: Daehee
authors.initials: D
authors.lastname: Jung
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Sang J
authors.initials: SJ
authors.lastname: Park
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: Hong R
authors.initials: HR
authors.lastname: Cho
authors.forename: Byungsuk
authors.initials: B
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9