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Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.

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-?B 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 PPAR? 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 PPAR? 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.

SUBMITTER: Sun G

PROVIDER: S-EPMC5966453 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.

Sun Guangyong G Sun Xiaojing X Li Wei W Liu Kai K Tian Dan D Dong Yiran Y Sun Xuelian X Xu Hufeng H Zhang Dong D

Cell death & disease 20180523 6

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 ...[more]

PMID: 29795285

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Project description:The role of conventional TCR??+CD4+ or TCR??+CD8?+ single-positive (sp) T lymphocytes in adaptive immunity is well-recognized. However, non-conventional T cells expressing TCR?? or TCR?? but lacking CD4 and CD8? expression [i.e., CD4-CD8?- double-negative (dn) T cells] are thought to play a role at the interface between the innate and adaptive immune system. Dn T cells are frequent in swine, cattle or sheep and predominantly express TCR??. In contrast, TCR??+ T cells are rare in dogs. In this study, we identified a high proportion of canine dn T cells in the TCR??+ T cell population of PBMC, lymphatic and non-lymphatic organs. In PBMC, the frequency of this T cell subpopulation made up one third of the frequency of TCR??+CD4+ sp, and almost half of the frequency of TCR??+CD8?+ sp T cells (i.e., ~15% of all TCR??+ T cells). Among TCR??+CD4-CD8?- dn T cells of PBMC and tissues, FoxP3+ cells were identified indicating regulatory potential of this T cell subset. 80% of peripheral blood FoxP3+TCR??+CD4-CD8?- dn T cells co-expressed CD25, and, interestingly, also the FoxP3-negative TCR??+CD4-CD8?- dn T cells comprised ~34% CD25+ cells. Some of the FoxP3-positive TCR??+CD4-CD8?- dn T cells co-expressed GATA-3 suggesting stable function of regulatory T cells. The frequency of GATA-3 expression by FoxP3-TCR??+CD4-CD8?- dn T cells was even higher as compared with TCR??+CD4+ sp T cells (20.6% vs. 11.9%). Albeit lacking FoxP3 and CD25 expression, TCR??+CD4-CD8?- dn T cells also expressed substantial proportions of GATA-3. In addition, TCR??+CD4-CD8?- dn T cells produced IFN-? and IL-17A upon stimulation. T-bet and granzyme B were only weakly expressed by both dn T cell subsets. In conclusion, this study identifies two dn T cell subsets in the dog: (i) a large (~7.5% in Peyer's patches, ~15% in lung) population of TCR??+CD4-CD8?- dn T cells with subpopulations thereof showing an activated phenotype, high expression of FoxP3 or GATA-3 as well as production of IFN-? or IL-17A and (ii) a small TCR??+CD4-CD8?- dn T cell subset also expressing GATA-3 without production of IFN-? or IL-17A. It will be exciting to unravel the function of each subset during immune homeostasis and diseases of dogs.

Dataset Information

Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.

Publications

Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.

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