The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

Abstract

CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses.Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity. Keywords: CD4 + T cells r Costimulatory molecules r Immune regulation r Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site Introduction CTLA-4 is an important regulator of T-cell responses [1][2][3][4]. Its critical role is highlighted by CTLA-4 knockout mice, which develop a fatal lymphoproliferative disorder soon after birth, arising from a profound failure of T-cell homeostasis [5,6]. Despite these potent effects, the activities of CTLA-4 are only partially understood.CTLA-4 shares sequence homology and B7 ligands (CD80/CD86) with the costimulatory molecule, CD28, but differs by delivering inhibitory, rather than activating, signals to the T cells on which it is expressed as a receptor [7,8]. Upregulation of CTLA-4 on activated T cells provides a mechanism for negative Correspondence: Dr. Frank J. Ward e-mail: mmd475@abdn.ac.uk feedback to control their responses. However, not all its regulatory effects are explained by inhibitory costimulation, since CTLA-4 can also suppress activated effector T-cell populations without the need for them to express it [9,10]. This latter, cell-extrinsic mechanism has been largely attributed to CD4 + regulatory T (Treg)-cell subsets, which constitutively express high levels of CTLA-4, and require it for their regulatory function [11][12][13][14][15][16].How Treg cells might use CTLA-4 to regulate effector T-cell responses remains controversial. It has been suggested that CTLA-4 on Treg cells binds B7 and thus blocks CD28-mediated effector T-cell costimulation, or that it induces inhibitory mechanisms in the APC such as the IDO tryptophan catabolic enzyme * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1274-1285 Immunomodulation 1275 cas...

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