title: MS4A4B is a GITR-associated membrane adapter, expressed by regulatory T cells, which modulates T cell activation.
abstract: 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.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom. duncan.howie@path.ox.ac.uk
authors.forename: Duncan
authors.initials: D
authors.lastname: Howie
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Nolan
authors.forename: Stephen
authors.initials: S
authors.lastname: Daley
authors.forename: Emma
authors.initials: E
authors.lastname: Butterfield
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Adams
authors.forename: Hugo
authors.initials: H
authors.lastname: Garcia-Rueda
authors.forename: Claire
authors.initials: C
authors.lastname: Thompson
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Saunders
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tone
authors.forename: Masahide
authors.initials: M
authors.lastname: Tone
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D020869:Gene Expression Profiling; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008565:Membrane Proteins; C411486:Ms4a4b protein, mouse; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse