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Infection and Immunity, December 2008, p. 5834-5842, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00542-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cytotoxic-T-Lymphocyte-Associated Antigen 4 Blockade Abrogates Protection by Regulatory T Cells in a Mouse Model of Microbially Induced Innate Immune-Driven Colitis{triangledown}

Koichiro Watanabe,1,2 Varada P. Rao,1 Theofilos Poutahidis,1,3 Barry H. Rickman,1 Masahiro Ohtani,1 Shilu Xu,1 Arlin B. Rogers,1 Zhongming Ge,1 Bruce H. Horwitz,4 Toshio Fujioka,2 Susan E. Erdman,1*,{dagger} and James G. Fox1,5*,{dagger}

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts,1 Department of Gastroenterology and General Medicine, Faculty of Medicine, Oita University, Oita, Japan,2 Laboratory of Pathology, Aristotle University of Thessaloniki, Thessaloniki, Greece,3 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts,4 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts5

Received 2 May 2008/ Returned for modification 22 July 2008/ Accepted 18 September 2008

Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4+ CD25+ CD45RBlow regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2–/– mice without Treg cell transfer. Despite high numbers of Foxp3+ Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody-treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines gamma interferon and interleukin-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.

* Corresponding author. Mailing address: Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave., Building 16-825, Cambridge, MA 02139. Phone: (617) 253-1757. Fax: (617) 258-5708. E-mail for S. E. Erdman: serdman{at}mit.edu. E-mail for J. G. Fox: jgfox{at}mit.edu

{triangledown} Published ahead of print on 29 September 2008.

Editor: J. L. Flynn

{dagger} S.E.E. and J.G.F. contributed equally to this study.

Infection and Immunity, December 2008, p. 5834-5842, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00542-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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