title: Mature T cell responses are controlled by microRNA-142.
abstract: T cell proliferation is critical for immune responses; however, the molecular mechanisms that mediate the proliferative response are poorly understood. MicroRNAs (miRs) regulate various molecular processes, including development and function of the immune system. Here, utilizing multiple complementary genetic and molecular approaches, we investigated the contribution of a hematopoietic-specific miR, miR-142, in regulating T cell responses. T cell development was not affected in animals with a targeted deletion of Mir142; however, T cell proliferation was markedly reduced following stimulation both in vitro and in multiple murine models of graft-versus-host disease (GVHD). miR-142-deficient T cells demonstrated substantial cell-cycling defects, and microarray and bioinformatics analyses revealed upregulation of genes involved in cell cycling. Moreover, 2 predicted miR-142 target genes, the atypical E2F transcription factors E2f7 and E2f8, were most highly upregulated in miR-142-deficient cells. Clustered regularly interspaced short palindromic repeat interference-mediated (CRISPRi-mediated) silencing of E2F7 and E2F8 in miR-142-deficient T cells ameliorated cell-cycling defects and reduced GVHD, and overexpression of these factors in WT T cells inhibited the proliferative response. Together, these results identify a link between hematopoietic-specific miR-142 and atypical E2F transcription factors in the regulation of mature T cell cycling and suggest that targeting this interaction may be relevant for mitigating GVHD.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Katherine
authors.initials: K
authors.lastname: Oravecz-Wilson
authors.forename: Nathan
authors.initials: N
authors.lastname: Mathewson
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: McEachin
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.forename: Julia
authors.initials: J
authors.lastname: Wu
authors.forename: Corinne
authors.initials: C
authors.lastname: Rossi
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Thomas
authors.initials: T
authors.lastname: Saunders
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D064591:Allografts; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D050702:E2F7 Transcription Factor / Q000235:genetics; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D050702:E2F7 Transcription Factor; C504722:E2F8 protein, mouse; C479901:E2f7 protein, mouse; D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse; D012097:Repressor Proteins