Allogeneic T cell responses are regulated  by a specific miRNA-mRNA network.
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.
Yaping
Y
Sun
Isao
I
Tawara
Meng
M
Zhao
Zhaohui S
ZS
Qin
Tomomi
T
Toubai
Nathan
N
Mathewson
Hiroya
H
Tamaki
Evelyn
E
Nieves
Arul M
AM
Chinnaiyan
Pavan
P
Reddy
D064591:Allografts; D000818:Animals; D060565:Argonaute Proteins / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006086:Graft vs Host Disease; D047468:Immunoprecipitation; D007519:Isoantigens; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010744:Phosphoric Monoester Hydrolases / Q000276:immunology; D011506:Proteins / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*
D060565:Argonaute Proteins; D007519:Isoantigens; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D011506:Proteins; D012333:RNA, Messenger; C496335:WAPL protein, mouse; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases