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High affinity of interaction between superantigen and T cell receptor Vbeta molecules induces a high level and prolonged expansion of superantigen-reactive CD4+ T cells.

ABSTRACT: In mice implanted with an osmotic pump filled with the superantigen (SAG) staphylococcal enterotoxin A (SEA), the V?3(+)CD4(+) T cells exhibited a high level of expansion whereas the V?11(+)CD4(+) T cells exhibited a mild level of expansion. In contrast, in mice implanted with an osmotic pump filled with SE-like type P (SElP, 78.1% homologous with SEA), the V?11(+)CD4(+) T cells exhibited a high level of expansion while the V?3(+)CD4(+) T cells exhibited a low level of expansion, suggesting that the level of the SAG-induced response is determined by the affinities between the TCR V? molecules and SAG. Analyses using several hybrids of SEA and SElP showed that residue 206 of SEA determines the response levels of V?3(+)CD4(+) and V?11(+)CD4(+) T cells both in vitro and in vivo. Analyses using the above-mentioned hybrids showed that the binding affinities between SEA and the V?3/V?11 ? chains and between SEA-MHC class II-molecule complex and V?3(+)/V?11(+) CD4(+) T cells determines the response levels of the SAG-reactive T cells both in vitro and in vivo.

SUBMITTER: Omoe K

PROVIDER: S-EPMC2945535 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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High affinity of interaction between superantigen and T cell receptor Vbeta molecules induces a high level and prolonged expansion of superantigen-reactive CD4+ T cells.

Omoe Katsuhiko K Nunomura Wataru W Kato Hidehito H Li Zhong-Juan ZJ Igarashi Osamu O Araake Minako M Sano Keigo K Ono Hisaya K HK Abe Yohei Y Hu Dong-Liang DL Nakane Akio A Kiyono Hiroshi H Takakuwa Yuichi Y Shinagawa Kunihiro K Uchiyama Takehiko T Imanishi Ken'ichi K

The Journal of biological chemistry 20100727 40

In mice implanted with an osmotic pump filled with the superantigen (SAG) staphylococcal enterotoxin A (SEA), the Vβ3(+)CD4(+) T cells exhibited a high level of expansion whereas the Vβ11(+)CD4(+) T cells exhibited a mild level of expansion. In contrast, in mice implanted with an osmotic pump filled with SE-like type P (SElP, 78.1% homologous with SEA), the Vβ11(+)CD4(+) T cells exhibited a high level of expansion while the Vβ3(+)CD4(+) T cells exhibited a low level of expansion, suggesting that ...[more]

PMID: 20663890

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Project description:AimsTumour necrosis factor α (TNF-α) represents a classical pro-inflammatory cytokine, and its increased levels positively correlate with the severity of many cardiovascular diseases. Surprisingly, some heart failure patients receiving high doses of anti-TNF-α antibodies showed serious health worsening. This work aimed to examine the role of TNF-α signalling on the development and progression of myocarditis and heart-specific autoimmunity.Methods and resultsMice with genetic deletion of TNF-α (Tnf+/- and Tnf-/-) and littermate controls (Tnf+/+) were used to study myocarditis in the inducible and the transgenic T cell receptor (TCRM) models. Tnf+/- and Tnf-/- mice immunized with α-myosin heavy chain peptide (αMyHC) showed reduced myocarditis incidence, but the susceptible animals developed extensive inflammation in the heart. In the TCRM model, defective TNF-α production was associated with increased mortality at a young age due to cardiomyopathy and cardiac fibrosis. We could confirm that TNF-α as well as the secretome of antigen-activated heart-reactive effector CD4+ T (Teff) cells effectively activated the adhesive properties of cardiac microvascular endothelial cells (cMVECs). Our data suggested that TNF-α produced by endothelial in addition to Teff cells promoted leucocyte adhesion to activated cMVECs. Analysis of CD4+ T lymphocytes from both models of myocarditis showed a strongly increased fraction of Teff cells in hearts, spleens, and in the blood of Tnf+/- and Tnf-/- mice. Indeed, antigen-activated Tnf-/- Teff cells showed prolonged long-term survival and TNF-α cytokine-induced cell death of heart-reactive Teff.ConclusionTNF-α signalling promotes myocarditis development by activating cardiac endothelial cells. However, in the case of established disease, TNF-α protects from exacerbating cardiac inflammation by inducing activation-induced cell death of heart-reactive Teff. These data might explain the lack of success of standard anti-TNF-α therapy in heart failure patients and open perspectives for T cell-targeted approaches.

Dataset Information

High affinity of interaction between superantigen and T cell receptor Vbeta molecules induces a high level and prolonged expansion of superantigen-reactive CD4+ T cells.

Publications

High affinity of interaction between superantigen and T cell receptor Vbeta molecules induces a high level and prolonged expansion of superantigen-reactive CD4+ T cells.

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