Di Marco Barros, RP; (2017) Tissue-specific Butyrophilin-like Molecules are Master Regulators of Intraepithelial γδ T cell Composition. Doctoral thesis , UCL (University College London).

Preview

Text Thesis_Corrections_FINALDRAFT.pdf - Submitted Version Download (21MB) | Preview

Abstract

Many epithelial barriers are constitutively populated by large numbers of organ-specific γδ T cells that collectively make up a substantial proportion of the body’s T cells. In mice, these intraepithelial lymphocytes (IEL) display striking site-specific T cell receptor (TCR) Variable (V)γ chain usage, such that Vγ5+, Vγ6+ and Vγ7+ T cells form lifelong associations with the murine epidermis, uterine and the small intestinal epithelium, respectively. The maintenance of IEL composition is critically important to host physiology and its disruption in murine epidermis is associated with dysregulated cutaneous inflammation and heightened susceptibility to carcinogenesis. Furthermore, tumour-associated γδ T cell gene-expression signatures were recently found to be the greatest correlate with overall survival in a genome-wide expression analysis of ~18,000 human tumours. Thus, there is considerable interest in identifying molecules that regulate infiltration, composition and activation of tissue-resident γδ T cells. Skint1 is a Butyrophilin-like (Btnl) gene expressed by thymic medullary epithelium and suprabasal keratinocytes, which shapes DETC composition. However, as neither Skint1 nor DETC are conserved, a general mechanism by which epithelia shape IEL composition remains unelucidated. Here we show that enterocyte Btnl1 expression shapes small intestinal IEL composition by driving extrathymic maturation and expansion of Vγ7+ IEL in trans upon their arrival in the gut. Uninfluenced by microbial or solid food antigens, this mechanism evokes the Major Histocompatibility Complex-driven selection of αβ T cell repertoires. Consistent with this, we show that Btnl1 together with Btnl6 elicits specific TCR-dependent responses of intestinal Vγ7+ cells in vitro. From these data, a generalizable mechanism emerges whereby organ-specific expression of Btnl molecules enables epithelial cells to actively shape the lifelong composition of their signature IEL compartments. Moreover, by identifying selection elements that regulate signature γδ IEL, our models also provide novel avenues to study the unique contributions of discreet IEL compartments to host immunity.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item