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.