Abstract
CD4+ T-cell-converted CD4−CD8− double negative (cDNT) have strong suppressive activity in the maintenance of immune tolerance, whereas IL-2 promotes cDNT proliferation and enhances cDNT resistance to apoptosis. However, the intrinsic mechanisms that regulate the survival of cDNT are still unknown. Here we demonstrate that the OX40 molecule was highly expressed on cDNT. The expression of OX40 was necessary to promote proliferation and inhibit apoptosis of cDNT in vivo and in vitro. OX40 promoted the survival of cDNT by regulating the expression of Bcl-2, Bcl-xL, Survivin, and BCL2L11. Canonical NF-κB cell signaling played an important role in the transmission of essential division and survival signals through OX40 in cDNT. IL-2 promoted the survival of cDNT in part via elevating the expression of the OX40 molecule. IL-2 promoted OX40 expression via downregulating the PPARα expression. In conclusion, we elucidated that OX40 is a key molecule that regulates cDNT proliferation and survival. IL-2 promoted OX40 expression by downregulating the PPARα binding to the OX40 promoter, leading to the elevated expression of Bcl-2, Bcl-xL, and Survivin in cDNT, which finally resulted in the promoted proliferation and decreased apoptosis of cDNT.
Highlights
Introduction RegulatoryCD4−CD8− double-negative T cells (DNT), which express αβ T-cell receptor (TCR) but do not express natural killer (NK) cell markers compose only a small population of T lymphocytes (1–5%) in the peripheral blood and lymphoid organs of rodents and humans[1,2]
OX40 molecule was highly expressed on converted DNT (cDNT) and was necessary to promote proliferation and inhibit apoptosis of cDNT As we reported[3], after 7 days’ in vitro stimulation with mature dendritic cells (DCs), approximately 30% of CD4 T cells lost CD4 expression and became DNT (Fig. 1a, left)
By monitoring the apoptosis of activated CD4+ and cDNT, we found that the percentage of Annexin V+ cells was markedly lower in the cDNT than in activated CD4+ T cells (51.7 ± 5.7% vs. 8.1 ± 4.2%, P < 0.05, Fig. 1a, right)
Summary
Introduction RegulatoryCD4−CD8− double-negative T cells (DNT), which express αβ T-cell receptor (TCR) but do not express natural killer (NK) cell markers compose only a small population of T lymphocytes (1–5%) in the peripheral blood and lymphoid organs of rodents and humans[1,2]. DNT cells have strong suppressive activity toward CD4+ T cells and CD8+ T cells[3,4,5,6], as well as B cells[4,7], dendritic cells (DCs)[8], and NK cells[9], which are capable of suppressing the immune response and exert. The over-activated CD4+ T cells can be converted into DNT in vivo[15]. The CD4 T-cell-converted DNT (cDNT) are CD25+, CD44+, CD69+, and Foxp3−. These cDNT potently suppressed vigorous allo- and autoimmune responses, prolonged islet and skin allograft survival, and prevented and cured autoimmune type 1 diabetes with antigen-specificity[3,6,16]
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