Th130 - Interleukin-1beta Enables Endothelial Surface Expression and Trans-presentation of Interleukin -15 by Relieving let-7c-3p-mediated Translational Suppression

Luanna Summer – Yale School of Medicine; Francesc Lopez – Yale School of Medicine; Zuzana Tobiasova – Yale School of Medicine; Thomas Manes – Yale School of Medicine; Shruthi Yasothan – University of Cambridge; Guiyu Song – Yale School of Medicine; Daniel Jane-wit – Yale School of Medicine; W. Mark Saltzman – Yale School of Medicine; Jordan Pober – Yale School of Medicine

Abstract Text: Expression of interleukin-15 (IL-15) on the surface of human graft endothelial cells (ECs) bound to the IL-15 receptor alpha (IL-15Ralpha) subunit can increase the activation of cytotoxic T lymphocytes (CTLs), potentiating allograft rejection. Surface expression of this complex can be induced by alloantibody-mediated complement activation and, ultimately, autocrine/paracrine IL-1-mediated activation of NF-kappaB. We identify 8 constitutively expressed alternatively spliced IL-15 transcripts in human ECs. IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA Polymerase II-mediated transcription while requiring new protein translation. By small RNA sequencing, we found that IL-1β causes an NF-kappaB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a translational block of IL-15 surface protein. Let7c-3p antagonist can induce EC surface expression of IL-15/IL-15Ralpha in the absence of complement activation or of IL-1, enabling IL-15 trans-presentation to boost CD8 T cell activation. The complexity of IL-15 regulation requires caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for trans-presentation.