Allogeneic T cell responses are regulated by a specific miRNA-mRNA network

• Authors: Yaping Sun, University of Michigan; Isao Tawara, Mie University Hospital; Meng Zhao, Emory University; Zhaohui Qin, Emory University; Tomomi Toubai, University of Michigan; Nathan Mathewson, University of Michigan; Hiroya Tamaki, University of Michigan; Evelyn Nieves, University of Michigan; Arul M. Chinnaiyan, University of Michigan; Pavan Reddy, University of Michigan
• Journal Title: Journal of Clinical Investigation
• Volume: Volume 123, Number 11
• Publisher: American Society for Clinical Investigation | 2013-11-01, Pages 4739-4754
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI70013
• Subjects: Health Sciences, Immunology; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; MEDICINE, RESEARCH & EXPERIMENTAL; MICRORNA TARGET PREDICTIONS; BONE-MARROW-TRANSPLANTATION; GENOME-WIDE ANALYSIS; VERSUS-HOST-DISEASE; MOUSE MODELS; MOLECULAR-MECHANISMS; BINDING PROTEIN; CO-STIMULATION; RIP-CHIP; ACTIVATION

Abstract

Donor T cells that respond to host alloantigens following allogeneic bone marrow transplantation (BMT) induce graft-versus-host (GVH) responses, but their molecular landscape is not well understood. MicroRNAs (miRNAs) regulate gene (mRNA) expression and fine-tune the molecular responses of T cells. We stimulated naive T cells with either allogeneic or nonspecific stimuli and used argonaute cross-linked immunoprecipitation (CLIP) with subsequent ChIP microarray analyses to profile miR responses and their direct mRNA targets. We identified a unique expression pattern of miRs and mRNAs following the allostimulation of T cells and a high correlation between the expression of the identified miRs and a reduction of their mRNA targets. miRs and mRNAs that were predicted to be differentially regulated in allogeneic T cells compared with nonspecifically stimulated T cells were validated in vitro. These analyses identified wings apartlike homolog (Wapal) and synaptojanin 1 (Synj1) as potential regulators of allogeneic T cell responses. The expression of these molecular targets in vivo was confirmed in MHC-mismatched experimental BMT. Targeted silencing of either Wapal or Synj1 prevented the development of GVH response, confirming a role for these regulators in allogeneic T cell responses. Thus, this genome-wide analysis of miRNA-mRNA interactions identifies previously unrecognized molecular regulators of T cell responses.