CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones

Harding, Fiona; McArthur, James G.; Gross, Jane A.; Raulet, David H.; Allison, James P.

doi:10.1038/356607a0

Cited by 1,454 publications

(898 citation statements)

References 17 publications

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“…The role of CD28 in cell-mediated immunity is demonstrated by the CD28 gene-knockout mouse, which has an immunosuppressed phenotype, and CD28 Ϫ/Ϫ mouse T cells are unable to sustain activation and are susceptible to apoptosis (2,3). In various experimental systems, blockade of CD28 interaction with its ligands CD80 and CD86 has been demonstrated to dampen antigenspecific immune responses (4).…”

Section: Conclusion Overproduction Of Tnf␣ In Ra Induces a Global Domentioning

confidence: 99%

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

Arthritis & Rheumatism

125

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Objective. The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4؉ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor ␣ (TNF␣). Previous in vitro studies have shown that TNF␣ induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNF␣.Methods. Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNF␣.Results. In addition to higher frequencies of CD28 null T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4؉,CD28؉ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNF␣ in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNF␣-neutralizing therapy.Conclusion. Overproduction of TNF␣ in RA induces a global down-regulation of CD28 in CD4؉ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.

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Section: Conclusion Overproduction Of Tnf␣ In Ra Induces a Global Domentioning

confidence: 99%

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

Arthritis & Rheumatism

125

View full text Add to dashboard Cite

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“…[5][6] In contrast, blockade of this pathway results in the induction of antigen-specific unresponsiveness, or anergy, both in vitro and in vivo. 7,8 However, several other T cell-APC interactions can also provide costimulation. One such interaction is mediated by cytotoxic T-lymphocyte antigen-4 (CTLA-4), which is structurally related to CD28, but it inhibits rather than enhances T-cell activation.…”

Section: Introductionmentioning

confidence: 99%

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Zhu

Gao

et al. 2010

Cell Mol Immunol

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CD28 is one of the costimulatory molecules crucial for T-cell activation and thus has become an attractive target for therapeutic immunomodulation. Conventional strategies for blocking CD28 activity using monoclonal antibodies, Fab fragments, antagonistic peptide and fusion proteins, have apparent disadvantages such as inherent immunogenicity, unwanted Fc signaling, poor tissue penetration and bioinstability. Recent research has been directed toward the creation of non-natural, sequence-specific biomimetic oligomers with bioinspired structures that capture the amino-acid interface of the targeted proteins. One such family of molecules is the poly-N-substituted glycines or peptoids, which have close structural similarity to peptides but are essentially invulnerable to protease degradation. To screen for peptoids that specifically target CD28, we first designed and chemically synthesized 19 candidate peptoids based on molecular modeling and docking. Using the phage-displaying system that expresses the extracellular domain of the CD28 homodimer and contains the core B7-binding motif, a peptoid (No. 9) with a molecular formula of C 21 H 29 N 3 O 7 , was identified to display the highest binding activity to CD28. This peptoid not only inhibited the lymphocyte proliferation in vitro, but suppressed immunoresponses against alloantigens in vivo, and attenuated the graft-versus-host disease in a mouse bone-marrow transplantation model. These results suggested that peptoids targeting CD28 are effective agents for blocking the CD28-mediated costimulation and suitable for development of novel therapeutic approaches for diseases involving this pathway.

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“…An optimal T cell activation requires two signals, the first signal through the ligation of TCR/CD3 complex and the second costimulatory signal delivered by direct interaction between T cells and antigen-presenting cells (APC). Triggering of TCR/CD3 alone, in the absence of a costimulatory signal, not only fails to induce proliferation but occasionally leads to a state of hyporesponsiveness or anergy [1,2,6]. One of the best known, a crucial costimulatory molecule, is CD28, which is expressed on most T cells and thymocytes.…”

Section: Introductionmentioning

confidence: 99%

Preferential elimination of CD28+ T cells in systemic lupus erythematosus (SLE) and the relation with activation-induced apoptosis

Kaneko

Saito

Hashimoto

et al. 1996

Clinical and Experimental Immunology

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SUMMARYCD28 on T cells provides a potent costimulatory signal for T cell activation. Down-regulation of CD28 on peripheral T cells has been reported in certain clinical conditions, but full studies on the mechanism and biological significance have not been performed. Our extensive phenotype analysis of peripheral blood lymphocytes (PBL) from SLE patients revealed that the absolute number of CD28 T cells of both CD4 and CD8 phenotypes was selectively decreased, while that of CD28 ÿ T cells was maintained. CD28 T cells from SLE patients exhibited mostly normal proliferative responses to both CD28-dependent and -independent stimulations. In contrast, CD28 ÿ T cells were hyporesponsive to anti-CD3 stimulation in both SLE and normal controls. These results implied that the selective decrease of CD28 T cells in SLE does not result from a hyporesponsiveness of CD28 T cells. To investigate the reason for the selective loss of CD28 T cells, we determined the appearance of apoptotic cells in culture with or without anti-CD3 stimulation. Apoptotic cells defined by merocyanine (MC)540 were gradually increased from 12 h to 24 h. Anti-CD3-induced apoptosis of CD28 T cells was significantly accelerated in SLE, whereas apoptosis of CD28 ÿ T cells was hardly detected in both SLE and normal controls. Comparative analysis between CD28 and CD28 ÿ T cells on CD95 (Fas) and Bcl-2 expression, which are related to activation-induced cell death (AICD), did not show a major difference, although CTLA4, which has been demonstrated to transmit an apoptosis-inducing signal, was expressed only on CD28 T cells. Our results suggest that CD28-mediated costimulation influences T cell susceptibility to AICD and may be involved in T cell lymphopenia in SLE.

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CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones

Cited by 1,454 publications

References 17 publications

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Preferential elimination of CD28+ T cells in systemic lupus erythematosus (SLE) and the relation with activation-induced apoptosis

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