MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the post-transcriptional expression of target genes. There is ample evidence that miRNAs are involved in the regulation of the immune response including after transplantation. In previous studies, miR-182 was found to be significantly increased during graft rejection. Expression of miR-182 is dependent on combined TCR and IL-2 signaling through STAT5. The transcription factor Foxo1 is a target of miR-182, and miR-182 represses Foxo1 to promote clonal expansion of activated helper T lymphocytes. Recent studies indicate that miR-182 promotes Th17 cell pathogenicity also through repression of Foxo1. Since miR-182 has been demonstrated to affect T cell responses and to be increased during graft rejection in both experimental models and clinical transplants, we sought to examine the role of this miRNA after transplantation in the absence and presence of immunosuppression. To determine if miR-182 contributes to graft rejection, groups (n=5) of wild-type C57BL/6 (WT) or miR-182^-/- mice (H-2^b) received BALB/c cardiac allografts and were monitored for graft survival. miR-182^-/- recipients had a two-day prolongation of graft survival (6.4 days WT, vs. 8.2 days miR-182^-/-, P<0.01). We then examined whether co-stimulation blockade would further prolong graft survival in the absence of miR-182. Groups of WT (n=7) or miR-182^-/- (n=8) recipients of BALB/c hearts were treated with CTLA4-Ig. Graft survival was significantly increased in miR-182^-/- recipients treated with CTLA4-Ig (60 days miR-182^-/- vs. 31 days WT, P<0.01). To define the mechanism for this prolonged graft survival we examined T cell phenotypes in groups (n=3) of WT and miR-182^-/- allograft recipients treated with CTLA4-Ig. While the percentages of naïve and effector cells were similar, there was a dramatic and highly significant reduction in memory T cells (CD4⁺CD44^hiCD62L^int), in miR-182^−/− recipients treated with CTLA4-Ig (4.8% ± 0.4 WT vs. 0.1% ± 0.1 miR-182^−/−;P < 0.01) suggesting miR-182 contributes to the generation of memory T cells. In summary, we report for the first time the synergistic effect of a specific miRNA and co-stimulation blockade on allograft survival. Further, our results support a mechanism whereby modulation of Foxo1 may contribute to graft outcomes. Modulation of selective miRNAs may prove to be an efficacious strategy along with co-stimulation blockade, to augment graft survival.

CITATION INFORMATION: Kaul V, Wei L, Qu X, Martinez O, Krams S. Memory T Cells Are Decreased in Transplant Recipients Deficient in miR-182. Am J Transplant. 2017;17 (suppl 3).

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