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International Immunology Advance Access originally published online on February 28, 2008
International Immunology 2008 20(4):577-589; doi:10.1093/intimm/dxn016
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

CD4+ICOS+ T lymphocytes inhibit T cell activation ‘in vitro’ and attenuate autoimmune encephalitis ‘in vivo’

Jose M. Rojo1, Eliana Pini2, Gloria Ojeda2, Raquel Bello1, Chen Dong3, Richard A. Flavell4,5, Umberto Dianzani6 and Pilar Portolés2

1 Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, E-28040 Madrid, Spain
2 Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, E-28220 Madrid, Spain
3 Department of Immunology, M. D. Anderson Cancer Centre, 7455 Fannin, Unit 902, Houston, TX 77030-1903, USA
4 Howard Hughes Medical Institute
5 Department of Immunobiology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA
6 Department of Medical Sciences, ‘A. Avogadro’ University of Eastern Piedmont, Via Solaroli 17, I-28100 Novara, Italy

Correspondence to: J. M. Rojo; E-mail: jmrojo{at}cib.csic.es

The inducible co-stimulator (ICOS, CD278) is essential to the efficient development of normal and pathological immune reactions. Since ICOS-deficient mice have enhanced susceptibility to experimental allergic encephalomyelitis (EAE), we have functionally analyzed a CD4+ICOS+ population comprising 6–15% of all CD4+ T cells in secondary lymphoid organs of unmanipulated wild-type mice and checked for their ability to suppress EAE. In C57BL/6 mice, CD4+ICOS+ cells were a major source of cytokines including IFN-{gamma}, IL-2, IL-4, IL-10 or IL-17A. Upon activation, these cells showed preferentially enhanced production of IL-4 or IL-10 but inhibited IFN-{gamma} production. In contrast, CD4+ICOS– cells mainly produced IFN-{gamma}. Interestingly, CD4+ICOS+ cells partially suppressed the proliferation of CD4+ICOS– or CD4+CD25– lymphocytes ‘in vitro’ by an IL-10-dependent mechanism. Furthermore, CD4+ICOS+ activated and expanded under appropriate conditions yielded a population enriched in cells producing IL-10 and Th2 cytokines that also suppressed the proliferation of CD4+CD25– lymphocytes. CD4+ICOS+ cells, before or after expansion in vitro, reduced the severity of EAE when transferred to ICOS-deficient mice. In the same EAE model, lymph node cells from ICOS-deficient mice receiving ICOS+ cells showed reduced IL-17A production and enhanced IL-10 secretion upon antigen activation in vitro. Thus, naturally occurring CD4+ICOS+ cells, expanded or not in vitro, are functionally relevant cells able of protecting ICOS-deficient mice from severe EAE.

Keywords: CD278, EAE, ICOS, inducible co-stimulator, regulatory T cells

Transmitting editor: L. Moretta

Received 17 May 2007, revised 12 December 2007, accepted 23 January 2008.


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