Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis

C. Coquerelle, G. Oldenhove, V. Acolty, J. Denoeud, G. Vansanten, J. M. Verdebout, A. Mellor, J. A. Bluestone, M. Moser

Research output: Contribution to journalArticle

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Abstract

Background and aims: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to act as a negative regulator of T cell function and has been implicated in the regulation of T helper 1 (Th1)/Th2 development and the function of regulatory T cells. Tests were carried out to determine whether anti-CTLA-4 treatment would alter the polarisation of naive T cells in vivo. Methods: Mice were treated with anti-CTLA-4 monoclonal antibody (mAb) (UC10-4F10) at the time of immunisation or colonic instillation of trinitrobenzene sulfonic acid (TNBS). The cytokines produced by lymph node cells after in vitro antigenic stimulation and the role of indoleamine 2,3 dioxygenase (IDO) and of interleukin-10 (IL-10) were tested, and the survival of mice was monitored. Results: Injection of anti-CTLA-4 mAb in mice during priming induced the development of adaptive CD4+ regulatory T cells which expressed high levels of ICOS (inducible co-stimulator), secreted IL-4 and IL-10. This treatment inhibited Th1 memory responses in vivo and repressed experimental intestinal inflammation. The anti-CTLA-4-induced amelioration of disease correlated with IDO expression and infiltration of ICOShigh Foxp3+ T cells in the intestine, suggesting that anti-CTLA-4 acted indirectly through the development of regulatory T cells producing IL-10 and inducing IDO. Conclusions: These observations emphasise the synergy between IL-10 and IDO as anti-inflammatory agents and highlight anti-CTLA-4 treatment as a potential novel immunotherapeutic approach for inducing adaptive regulatory T cells.

Original languageEnglish (US)
Pages (from-to)1363-1373
Number of pages11
JournalGut
Volume58
Issue number10
DOIs
StatePublished - Oct 1 2009

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Inducible T-Cell Co-Stimulator Protein
CTLA-4 Antigen
Indoleamine-Pyrrole 2,3,-Dioxygenase
Regulatory T-Lymphocytes
Colitis
Interleukin-10
Anti-Inflammatory Agents
T-Lymphocytes
Therapeutics
Monoclonal Antibodies
Trinitrobenzenes
Sulfonic Acids
Thomsen-Friedenreich antibodies
Interleukin-4
Intestines
Immunization
Lymph Nodes
Cytokines
Inflammation
Injections

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Coquerelle, C., Oldenhove, G., Acolty, V., Denoeud, J., Vansanten, G., Verdebout, J. M., ... Moser, M. (2009). Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis. Gut, 58(10), 1363-1373. https://doi.org/10.1136/gut.2008.162842

Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis. / Coquerelle, C.; Oldenhove, G.; Acolty, V.; Denoeud, J.; Vansanten, G.; Verdebout, J. M.; Mellor, A.; Bluestone, J. A.; Moser, M.

In: Gut, Vol. 58, No. 10, 01.10.2009, p. 1363-1373.

Research output: Contribution to journalArticle

Coquerelle, C, Oldenhove, G, Acolty, V, Denoeud, J, Vansanten, G, Verdebout, JM, Mellor, A, Bluestone, JA & Moser, M 2009, 'Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis', Gut, vol. 58, no. 10, pp. 1363-1373. https://doi.org/10.1136/gut.2008.162842
Coquerelle, C. ; Oldenhove, G. ; Acolty, V. ; Denoeud, J. ; Vansanten, G. ; Verdebout, J. M. ; Mellor, A. ; Bluestone, J. A. ; Moser, M. / Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis. In: Gut. 2009 ; Vol. 58, No. 10. pp. 1363-1373.
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AU - Oldenhove, G.

AU - Acolty, V.

AU - Denoeud, J.

AU - Vansanten, G.

AU - Verdebout, J. M.

AU - Mellor, A.

AU - Bluestone, J. A.

AU - Moser, M.

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N2 - Background and aims: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to act as a negative regulator of T cell function and has been implicated in the regulation of T helper 1 (Th1)/Th2 development and the function of regulatory T cells. Tests were carried out to determine whether anti-CTLA-4 treatment would alter the polarisation of naive T cells in vivo. Methods: Mice were treated with anti-CTLA-4 monoclonal antibody (mAb) (UC10-4F10) at the time of immunisation or colonic instillation of trinitrobenzene sulfonic acid (TNBS). The cytokines produced by lymph node cells after in vitro antigenic stimulation and the role of indoleamine 2,3 dioxygenase (IDO) and of interleukin-10 (IL-10) were tested, and the survival of mice was monitored. Results: Injection of anti-CTLA-4 mAb in mice during priming induced the development of adaptive CD4+ regulatory T cells which expressed high levels of ICOS (inducible co-stimulator), secreted IL-4 and IL-10. This treatment inhibited Th1 memory responses in vivo and repressed experimental intestinal inflammation. The anti-CTLA-4-induced amelioration of disease correlated with IDO expression and infiltration of ICOShigh Foxp3+ T cells in the intestine, suggesting that anti-CTLA-4 acted indirectly through the development of regulatory T cells producing IL-10 and inducing IDO. Conclusions: These observations emphasise the synergy between IL-10 and IDO as anti-inflammatory agents and highlight anti-CTLA-4 treatment as a potential novel immunotherapeutic approach for inducing adaptive regulatory T cells.

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