*Purpose: CD57 expression has been shown to identify a subset of memory T cells that are resistant to CD28/B7 costimulation blockade (B7CoB). This study was to explore the phenotype-function relationships of T cells with specific focus on CD57⁺ cells and the role of miR17-92 in costimulation resistant effector memory T cell-mediated alloresponses.

*Methods: CD57⁺ T cells were purified from healthy individuals and characterized by flow cytometry and RT-PCR. To define the role of miR17-92 in allospecific immunity, miR17-92 deficient C57BL/6 mice (miR17-92^f/fCD4-Cre) were generated by crossing floxed miR17-92 C57BL/6 mice with CD4-Cre C57BL/6 mice, and evaluated in a MHC-mismatched murine heart transplantation model using BALB/c mice as donors.

*Results: CD57⁺ cells demonstrated lower surface TCR expression than CD57^– cells and were more sensitive to TCR signaling (required less costimulation) with significant higher levels of ZAP70 phosphorylation (CD4⁺ cells p<003, CD8⁺ cells p<0.0019) than CD57^– cells. Additional study revealed that the expression of the miR17-92-cluster, an important micro-RNA cluster controlling Th1 responses, was significantly lower in CD57⁺ cells than CD57^– cells (p<0.05). C57BL/6 mice (n=7) without treatment rejected allografts with median survival of 8 days. Transient B7CoB with a single 250 μg dose of CTLA-4-Ig (n=8) moderately prolonged allograft survival (median survival of 19.5 days). miR17-92^f/fCD4-Cre mice without treatment (n=6) had similar allograft survival compared with untreated C57BL/6 mice. In contrast, miR17-92^f/fCD4-Cre mice with transient B7CoB (n=7) significantly (p<0.0001) prolonged allograft survival (median survival=71 days) when compared with C57BL/6 mice (n=7) with transient B7CoB. Untreated C57BL/6 mice showed a marked increase of CD8⁺ effector memory cells (T_EM) at the time of rejection (68.9±20%). B7CoB significantly reduced the frequency of CD8⁺ T_EM (p<0.003) in C57BL/6 mice (17.2±8.6%) when compared with untreated controls, and miR17-92^f/fCD4-Cre mice treated with transient B7CoB showed further reduction in CD8⁺ T_EM cells (9.7±3.9%).

*Conclusions: The expression of the miR17-92 cluster is lower in CD57⁺ cells. Depleting miR17-92 cluster in MHC mismatched murine heart transplantation prolongs allograft survival in B7CoB treated mice and inhibits the development of alloresponsive T_EM cells. Our data warrant comprehensive evaluation in targeting miR17-92 cluster and its signaling pathway to prevent CoB-resistant allospecific immunity

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