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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901070v1 183/7/4197    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Howie, D. Articles by Waldmann, H. PubMed PubMed Citation Articles by Howie, D. Articles by Waldmann, H. Pubmed/NCBI databases Substance via MeSH

MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation¹

Duncan Howie^2,*, Kathleen F. Nolan^*, Stephen Daley^*, Emma Butterfield^*, Elizabeth Adams^*, Hugo Garcia-Rueda^*, Claire Thompson^*, Nigel J. Saunders^*, Stephen P. Cobbold^*, Yukiko Tone, Masahide Tone and Herman Waldmann^*

^* Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

In the aftermath of thymic negative selection, natural and adaptive regulatory T cells (Tregs) must acknowledge peripheral, "danger-free" self-Ag to ensure their sustained activity. In this paper, we show that natural and adaptive Tregs or T cells transduced with cDNA for Foxp3, just like Th1 cells, express members of the MS4A family of transmembrane molecules. Naive T cells transduced with MS4A4B become able to respond to lower levels of Ag. Using two family members, MS4A4B and MS4A6B, as baits in a yeast split-ubiquitin Treg library screen, we demonstrate their interaction with each other and with GITR, Orai1, and other surface receptors. Interaction of 4B with GITR augments GITR signaling and T cell IL-2 production in response to triggering with GITR ligand or anti-GITR Abs. This interaction provides a mechanism whereby MS4A family members, through lateral coassociation with costimulatory molecules, may amplify Ag signals. We propose that T cells preoccupied with immune defense use this MS4A family to enhance sensitivity to extrinsic Ag stimulation, ensuring its elimination, while Tregs use these adaptors to allow low level Ag signals to sustain regulatory 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 funded by a programme grant from the Medical Research Council and a grant from the EU FP6 RISET consortium.

² Address correspondence and reprint requests to Dr. Duncan Howie, Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom. E-mail address: duncan.howie{at}path.ox.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; BMDC, bone marrow-derived dendritic cell; DBY, cells stimulated without exogenous human TGFβ; DBYT, cells stimulated with exogenous human TGFβ; DC, dendritic cell; iTreg, TGFβ-induced Tregs; nTreg, natural Treg; SAGE, serial analysis of gene expression.

⁴ The online version of this article contains supplemental material.