Butyrophilins: an emerging family of immune regulators Lucie Abeler-Do ¨ rner 1, 2, 3 , Mahima Swamy 1, 2 , Gareth Williams 4 , Adrian C. Hayday 1, 2, 3 and Anna Bas 5 1 Peter Gorer Department of Immunobiology, King’s College School of Medicine, Guy’s Hospital, London SE1 9RT, UK 2 London Research Institute, Cancer Research United Kingdom, London WC2A 3PX, UK 3 Biomedical Research Centre of Guy’s and St Thomas’ Hospitals at King’s College, London SE1 9RT, UK 4 The Wolfson Centre for Age-Related Diseases, King’s College, London SE1 1UL, UK 5 Mucosal Immunobiology and Vaccine Center (MIVAC), Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Box 435, S-405 30 Gothenburg, Sweden Butyrophilins (Btns) and butyrophilin-like (Btnl) mole- cules are emerging as novel regulators of immune responses in mice and humans. Several clues point to their probable importance: many of the genes are locat- ed within the MHC; they are structurally related to B7- co-stimulatory molecules; they are functionally impli- cated in T cell inhibition and in the modulation of epithelial cell–T cell interactions; and they are geneti- cally associated with inflammatory diseases. Nonethe- less, initial immersion into the current literature can uncover confusion over even basic information such as gene names and expression patterns, and seemingly conflicting data regarding the biological activities of different family members. This review addresses each of these issues, concluding with the attractive potential of Btn and Btnl molecules to act as specific attenuators of tissue-associated inflammatory responses. Butyrophilin (Btn) and butyrophilin-like (Btnl) genes belong to the expanding family of co-stimulatory molecules Thirty years ago, an appropriate focus of the immunologi- cal community was on elucidating the molecular basis of antigen recognition by T cells. However, shortly thereafter it became clear that antigen engagement is insufficient to activate T cells and that co-stimulation through receptors such as CD28 was also required [1]. Rather than playing second fiddle to T cell antigen receptor (TCR) biology, co- stimulation has proved to be of fundamental importance. For example, the initial and defining activity of Toll-like receptor (TLR) engagement by microbial molecules was to upregulate on antigen presenting cells (APCs) the ligands for CD28, known as B7-1 and B7-2 (CD80 and CD86, respectively, in humans) [2]. Furthermore, it soon became apparent that the activation of T cells was only one side of co-stimulation; the other being the capacity of co-stimula- tory molecules to inhibit T cell activation by engaging an alternative receptor. For example, cytotoxic T lymphocyte antigen (CTLA)-4 is upregulated on activated T cells and competes with CD28 for B7 molecules, thereby attenuating the effector T cell response. Of note, clinical reagents that block this and other negative co-stimulatory activities are proving highly efficacious at reactivating T cell responses in tumour-bearing patients [3,4]. Thus, there is intense interest in identifying other co-stimulatory molecules; par- ticularly ones that might target immune and inflammatory responses in specific tissues, rather than having broad systemic effect. In this context, sequencing of the human and murine genome has identified novel B7-related molecules, with the Btn and Btnl genes being the most recently described [5–9]. Fuelled by the genetic association of human BTNL2 with pathological conditions such as sarcoidosis and ulcerative colitis [10], independent studies over the past 5 years have identified immunological functions for several Btn and Btnl family members; perhaps the most important being their capacity to regulate peripheral and tissue-associated T cells including unconventional T cells [2,3,5,7,13,16]. This review examines the current literature on Btn and Btnl molecules including genetic features, RNA and pro- tein expression patterns, and functional data that link Btn and Btnl molecules with immune regulation in health and disease. Chromosomal localisation and structure of the Btn and Btnl genes and their products The Btn and Btnl proteins are characterised by their similarity to the first identified family member, butyrophi- lin (BTN1A1), and several of their genes are conserved in mice and humans. Moreover, the Btn and Btnl family is very similar to the recently described murine Skint family, and most profoundly to the founding member Skint1, which drives the selective intrathymic differentiation of Vg5Vd1 + cells that will form the intraepidermal T cell compartment [11–13] (Figure 1a). The seven human BTN genes are clustered in the MHC class I region of chromosome 6 [13,14] and are divided into three subfamilies that form phylogenetically associated groups: BTN1, BTN2 and BTN3 (Figure 1b). The BTN1 subfamily contains only the prototypic single-copy BTN1A1 gene, whereas the BTN2 and BTN3 subfamilies each contain three genes BTN2A1, BTN2A2 and BTN2A3, and BTN3A1, BTN3A2 and BTN3A3, respectively (note that BTN2A3 is a pseudogene). The BTN proteins are Review Corresponding author: Bas, A. (anna.bas@gu.se). TREIMM-900; No. of Pages 8 1471-4906/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2011.09.007 Trends in Immunology xx (2011) 1–8 1