Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


J Immunol

Publication Date





4197 - 4204


Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, CHO Cells, Cell Line, Cricetinae, Cricetulus, Gene Expression Profiling, Glucocorticoid-Induced TNFR-Related Protein, Humans, Lymphocyte Activation, Membrane Proteins, Mice, Mice, Inbred CBA, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, T-Lymphocytes, Regulatory, Up-Regulation