Session Time: 4:30pm-6:00pm
Presentation Time: 5:42pm-5:54pm
Location: Room 306
*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 (miR17-92f/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). miR17-92f/fCD4-Cre mice without treatment (n=6) had similar allograft survival compared with untreated C57BL/6 mice. In contrast, miR17-92f/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 (TEM) at the time of rejection (68.9±20%). B7CoB significantly reduced the frequency of CD8+ TEM (p<0.003) in C57BL/6 mice (17.2±8.6%) when compared with untreated controls, and miR17-92f/fCD4-Cre mice treated with transient B7CoB showed further reduction in CD8+ TEM 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 TEM cells. Our data warrant comprehensive evaluation in targeting miR17-92 cluster and its signaling pathway to prevent CoB-resistant allospecific immunity
To cite this abstract in AMA style:Xu H, Guo Q, Song M, Miler A, Li Q, Kirk A. The mIR17-92 Cluster Promotes Costimulation Resistant Effector Memory T Cell-Mediated Alloresponses [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/the-mir17-92-cluster-promotes-costimulation-resistant-effector-memory-t-cell-mediated-alloresponses/. Accessed July 30, 2021.
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