Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes

Abstract

Although local regulation of T-cell responses by epithelial cells is increasingly viewed as important, few molecules mediating such regulation have been identified. Skint1, a recently identified member of the Ig-supergene family expressed by thymic epithelial cells and keratinocytes, specifies the murine epidermal intraepithelial lymphocyte (IEL) repertoire. Investigating whether Skint1-related molecules might regulate IEL in other compartments, this study focuses on buytrophilin-like 1 (Btnl1), which is conspicuously similar to Skint1 and primarily restricted to small intestinal epithelium. Btnl1 protein is mostly cytoplasmic, but surface expression can be induced, and in vivo Btnl1 can be detected adjacent to the IEL. In a newly developed culture system, enforced epithelial cell expression of Btnl1 attenuated the cells' response to activated IEL, as evidenced by suppression of IL-6 and other inflammatory mediators. These findings offer a unique perspective on emerging genetic data that Btnl genes may comprise novel and important local regulators of gut inflammation.epithelial immunity | intraepithelial lymphocyte-culture | B7 family | inflammation | immunosuppression

Regulation of Immunity by Butyrophilins

“…Murine Btnl1 has been detected in intestine, with a predominantly cytosolic localization (56), as well as in other lymphoid cells (57). Btnl1 suppressed inflammatory mediators in co-culture with murine epidermal IELs (56), and neutralizing antiBtnl1 antibodies caused enhanced immune pathology in mouse models of autoimmune disease, which, again, is consistent with negative regulatory effects on T cells (57).…”

Butyrophilins: an emerging family of immune regulators

“…An exception may be Btnl2, which presents an unusual arrangement of two IgV and two IgC domains, although alternative splice variants of Btnl2 have also been reported [7,16]. The predicted Btn and Btnl proteins differ from B7 and Skint molecules in their cytoplasmic tails, where, again with the exception of Btnl2, they possess an intracellular B30.2 domain [7,16,17], a composite of tandem PRY-SPRY domains [18].…”

“…Although only Btnl9 (68% overall, 65% extracellular identity) and Btnl2 (63% overall, 65% extracellular identity) are clear orthologues of human BTNL molecules (Figure 1), broad functional potentials may be conserved across the murine and human Btn and Btnl family. Although recent investigations have provided growing evidence for immune regulation by Btnl1 and Btnl2 [6,7,9,16], the functions of Btnl4, Btnl6 and Btnl9 remain to be thoroughly investigated. Note that Btnl5 and Btnl7 are predicted to be pseudogenes.…”

“…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 protein expression patterns, and functional data that link Btn and Btnl molecules with immune regulation in health and disease.…”

Mucosal T Cell Receptor γδ Intraepithelial T Cells

“…In this regard, the understanding of γδ IELs has been handicapped by the lack of a routine cell culture system in which could be studied their interactions with epithelial cells, DCs, and αβ T cells. Although progress in this direction has been periodically alluded to (Kapp et al, 2004;Bas et al, 2011), widely adopted cell culture studies and associated biochemistry have yet to make a profound impact on the study of γδ IELs. Until this issue is in some way resolved, it will remain difficult to paint molecular detail onto the interactions of γδ IELs with other cells that thereby compose a textbook model of γδ IEL actions within tissues.…”