Proliferating Cell Nuclear Antigen as the Cell Cycle Sensor for an HLA-Derived Peptide Blocking T Cell Proliferation

Self Cite

DQ 65–79, a peptide derived from residues 65–79 of the α-chain HLA class II molecule DQA03011, blocks T cell proliferation and induces T cell apoptosis. Using a yeast two-hybrid assay, we previously identified proliferating cell nuclear Ag (PCNA) as an intracellular ligand for DQ 65–79. In this study, we show that three regions of PCNA, residues 81–100, 121–140, and 241–261, interact with DQ 65–79. Residues 241–261 of PCNA also interact with the C terminus (residues 139–160) of the cell cycle regulator, p21, suggesting that DQ 65–79 and p21 might function similarly. We show here that DQ 65–79 competitively inhibits binding of p21 to PCNA and that both DQ 65–79 and p21 139–160 induce T cell apoptosis, suggesting that DQ 65–79 and p21 act similarly to inhibit cell growth.

Section: Coimmunoprecipitation Of Dq 65-79 and Pcnamentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

DQ 65–79, A Peptide Derived from HLA Class II, Mimics p21 to Block T Cell Proliferation

Dong

Lyu

Krensky

et al. 2003

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“…We have not yet determined whether DQ 65-79 has a similar effect on cyclin D1 transcription. We have shown that DQ 65-79 blocks cell cycle progression at the G 1 to S transition, in part by associating with proliferating cell nuclear Ag (53). In addition, DQ 65-79, through its effect on PI-3K, blocks degradation of p27, a negative regulator of cyclins (23,24).…”

Section: Discussionmentioning

confidence: 99%

DQ 65–79, a Peptide Derived from HLA Class II, Induces IκB Expression

Jiang¹,

Chen

Lyu³

et al. 2002

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A synthetic peptide corresponding to residues 65–79 of the α helix of the α-chain of the class II HLA molecule DQA03011 (DQ 65–79) inhibits the proliferation of human T lymphocytes in an allele nonrestricted manner. By using microarray technology, we found that expression of 29 genes was increased or decreased in a human CTL cell line after treatment with DQ 65–79. This study focuses on one of these genes, IκB-α, whose expression is increased by DQ 65–79. IκB proteins, including IκB-α and IκB-β, are increased in T cells treated with DQ 65–79. Nuclear translocation of the NF-κB subunits p65 and p50 is decreased in T cells after treatment with DQ 65–79, while elevated levels of p65 and p50 are present in cytosol. DQ 65–79 inhibits the degradation of IκB-α mRNA and inhibits the activity of IκB kinase. These findings indicate that the DQ 65–79 peptide increases the level of IκB proteins, thereby preventing nuclear translocation of the transcription factor, NF-κB, and inhibiting T cell proliferation.

“…Although MHC-derived peptides typically bind within the groove of the MHC molecule, thereby influencing the immune response, studies by our group and others have shown that MHCderived peptides may also exert their effects by binding to critical cell surface proteins participating in vital TCR-MHC interaction sites and intracellular proteins involved in the processing, presentation, and responses to Ag (6,7). Boytim et al (8) demonstrated that a synthetic peptide corresponding to the ␣1 ␣ helix of DQA03011 (DQ 65-79) inhibited alloantigen-induced T cell proliferation in an allele-independent manner (8) and DQ 65-79 bound to proliferating cell nuclear Ag, preventing cell cycle progression in a manner similar to that of rapamycin (9).…”

Section: Inhibition Of the Alloimmune Response Through The Generationmentioning

confidence: 99%

Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide

Zang¹,

Lin²,

Kalache³

et al. 2008

We have previously shown that HLA-DQA1, a peptide derived from a highly conserved region of MHC class II, prevents alloreactive T cell priming and effector function in vivo, although underlying mechanisms are obscure. In this study, we demonstrate that 28% of mice treated with HLA-DQA1 combined with low-dose rapamycin achieved permanent engraftment of fully MHC-disparate islet allografts and significantly prolonged survival in the remaining animals (log rank, p < 0.001). Immunohistologic examination of the grafts from HLA-DQA1/rapamycin-treated animals revealed up-regulated expression of TGF-ß and FoxP3. In vivo administration of blocking anti-TGF-ß or depleting anti-CD25 mAb augmented T cell alloimmunity and prevented the long-term engraft induced by HLA-DQA1. In vitro experiments further showed that HLA-DQA1 induced differentiation of CD4+ T cells into CD4+CD25+FoxP3+ regulatory T cells. Together, these data provide the first demonstration that HLA-DQA1, a MHC class II-derived peptide, can prolong allograft survival via a TGF-β and regulatory T cell-dependent mechanisms.