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* Molecular Immunology, Robert Koch Institute, Berlin, Germany;
Institute of Molecular and Cell Biology, Singapore, Republic of Singapore; and
Department of Biology, Millennium Pharmaceuticals, Cambridge, MA 02139
ICOS is an important regulator of T cell effector function. ICOS-deficient patients as well as knockout mice show severe defects in T cell-dependent B cell responses. Several in vitro and in vivo studies attributed this phenomenon to impaired up-regulation of cell surface communication molecules and cytokine synthesis by ICOS-deficient T cells. However, we now could show with Ag-specific T cells in a murine adoptive transfer system that signaling via ICOS does not significantly affect early T cell activation. Instead, ICOS substantially contributes to the survival and expansion of effector T cells upon local challenge with Ag and adjuvant. Importantly, the observed biological function of ICOS also extends to FoxP3+ regulatory T cells, as can be observed after systemic Ag delivery without adjuvant. In line with these findings, absence of ICOS under homeostatic conditions of nonimmunized mice leads to a reduced number of both effector-memory and FoxP3+ regulatory T cells. Based on these results, we propose a biological role for ICOS as a costimulatory, agonistic molecule for a variety of effector T cells with differing and partly opposing functional roles. This concept may reconcile a number of past in vivo studies with seemingly contradictory results on ICOS function.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants HU 1294/1 and Kr 827/13 from the German Research Foundation.
2 Current address: MedImmune, One MedImmune Way, Gaithersburg, MD 20878.
3 Address correspondence and reprint requests to Dr. Andreas Hutloff, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. E-mail address: hutloffa{at}rki.de
4 Abbreviations used in this paper: ICOS-L, ICOS ligand; KO, knockout; LN, lymph node; WT, wild type.
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