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Research Article Free access | 10.1172/JCI32562

Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice

Nicolas Degauque,1 Christophe Mariat,1 James Kenny,1 Dong Zhang,1 Wenda Gao,1 Minh Diem Vu,1 Sophoclis Alexopoulos,1 Mohammed Oukka,2 Dale T. Umetsu,3 Rosemarie H. DeKruyff,3 Vijay Kuchroo,2 Xin Xiao Zheng,1 and Terry B. Strom1

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

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1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

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1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

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1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Zhang, D. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Gao, W. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Vu, M. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Alexopoulos, S. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Oukka, M. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Umetsu, D. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by DeKruyff, R. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Kuchroo, V. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

Find articles by Zheng, X. in: PubMed | Google Scholar

1Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Division of Immunology, Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Terry B. Strom, Transplant Research Center, Beth Israel Deaconess Medical Center, H.I.M.-1, Room 1026, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.

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Published December 13, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI32562.
© 2007 The American Society for Clinical Investigation
Published December 13, 2007 - Version history
Received: May 2, 2007; Accepted: November 13, 2007
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Abstract

T cell Ig mucin (Tim) molecules modulate CD4+ T cell responses. In keeping with the view that Tim-1 generates a stimulatory signal for CD4+ T cell activation, we hypothesized that an agonist Tim-1–specific mAb would intensify the CD4+ T cell–dependant allograft response. Unexpectedly, we determined that a particular Tim-1–specific mAb exerted reciprocal effects upon the commitment of alloactivated T cells to regulatory and effector phenotypes. Commitment to the Th1 and Th17 phenotypes was fostered, whereas commitment to the Treg phenotype was hindered. Moreover, ligation of Tim-1 in vitro effectively deprogrammed Tregs and thus produced Tregs unable to control T cell responses. Overall, the effects of the agonist Tim-1–specific mAb on the allograft response stemmed from enhanced expansion and survival of T effector cells; a capacity to deprogram natural Tregs; and inhibition of the conversion of naive CD4+ T cells into Tregs. The reciprocal effects of agonist Tim-1–specific mAbs upon effector T cells and Tregs serve to prevent allogeneic transplant tolerance.

Version history
  • Version 1 (December 13, 2007): No description
  • Version 2 (February 1, 2008): No description
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