Allogeneic T cell responses are regulated by a specific miRNA-mRNA network
Yaping Sun, Isao Tawara, Meng Zhao, Zhaohui S. Qin, Tomomi Toubai, Nathan Mathewson, Hiroya Tamaki, Evelyn Nieves, Arul M. Chinnaiyan, Pavan Reddy
Yaping Sun, Isao Tawara, Meng Zhao, Zhaohui S. Qin, Tomomi Toubai, Nathan Mathewson, Hiroya Tamaki, Evelyn Nieves, Arul M. Chinnaiyan, Pavan Reddy
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Research Article Immunology

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

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 apart-like 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.

Authors

Yaping Sun, Isao Tawara, Meng Zhao, Zhaohui S. Qin, Tomomi Toubai, Nathan Mathewson, Hiroya Tamaki, Evelyn Nieves, Arul M. Chinnaiyan, Pavan Reddy

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