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HSP60 as a target of anti-ergotypic regulatory T cells.

Quintana FJ, Mimran A, Carmi P, Mor F, Cohen IR - PLoS ONE (2008)

Bottom Line: Anti-ergotypic T cells responded to T-cell HSP60 by proliferation and secreted IFNgamma and TGFbeta1.In vivo, adoptive transfer of an anti-ergotypic HSP60-specific T-cell line led to decreased secretion of IFNgamma by arthritogenic T cells and ameliorated adjuvant arthritis (AA).Thus, by functioning as an ergotope, HSP60 can control both the effector T cells and the regulatory HSP60-specific T cells that control them.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel. fquintana@rics.bwh.harvard.edu

ABSTRACT
The 60 kDa heat shock protein (HSP60) has been reported to influence T-cell responses in two ways: as a ligand of toll-like receptor 2 signalling and as an antigen. Here we describe a new mechanism of T-cell immuno-regulation focused on HSP60: HSP60 is up-regulated and presented by activated T cells (HSP60 is an ergotope) to regulatory (anti-ergotypic) T cells. Presentation of HSP60 by activated T cells was found to be MHC-restricted and dependent on accessory molecules - CD28, CD80 and CD86. Anti-ergotypic T cells responded to T-cell HSP60 by proliferation and secreted IFNgamma and TGFbeta1. In vitro, the anti-ergotypic T cells inhibited IFNgamma production by their activated T-cell targets. In vivo, adoptive transfer of an anti-ergotypic HSP60-specific T-cell line led to decreased secretion of IFNgamma by arthritogenic T cells and ameliorated adjuvant arthritis (AA). Thus, the presentation of HSP60 by activated T cells turns them into targets for anti-ergotypic regulatory T cells specific for HSP60. However, the direct interaction between the anti-ergotypic T regulators (anti-HSP60) and the activated T cells also down-regulated the regulators. Thus, by functioning as an ergotope, HSP60 can control both the effector T cells and the regulatory HSP60-specific T cells that control them.

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Anti-ergotypic HSP60-specific T cells become anergic after interacting with activated T cells.Anti-ergotypic Anti-p277 T cells were stimulated for 3 days with irradiated, activated A2b cells (A2b) or with irradiated APC fed with the p277 peptide (APC). The Anti-p277 T cells were maintained for 4 additional days in culture, and stimulated with APC and p277 peptide, Con A or immobilized anti-TCR (αTCR) antibodies. T-cell proliferation (A) and IFNγ (B) release were measured after 3 days. The proliferative responses are presented as the ΔCPM (±SEM) (A), and the IFNγ as pg/ml±SEM (B) of triplicate cultures. Three to five independent experiments produced similar results.
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pone-0004026-g008: Anti-ergotypic HSP60-specific T cells become anergic after interacting with activated T cells.Anti-ergotypic Anti-p277 T cells were stimulated for 3 days with irradiated, activated A2b cells (A2b) or with irradiated APC fed with the p277 peptide (APC). The Anti-p277 T cells were maintained for 4 additional days in culture, and stimulated with APC and p277 peptide, Con A or immobilized anti-TCR (αTCR) antibodies. T-cell proliferation (A) and IFNγ (B) release were measured after 3 days. The proliferative responses are presented as the ΔCPM (±SEM) (A), and the IFNγ as pg/ml±SEM (B) of triplicate cultures. Three to five independent experiments produced similar results.

Mentions: We have shown in the previous sections that HSP60-specific anti ergotypic T cells can recognize and down-regulate arthritogenic T cells, in vitro and in vivo. However, any regulatory mechanism has to be regulated; uncontrolled down-regulation of immunity would be as detrimental to the organism as uncontrolled autoimmunity [22]. We therefore studied whether the stimulation of HSP60-specific anti-erogotypic T cells by activated T cells might itself affect the regulators. In other words, might the anti-ergotypic HSP60-specific T-cell lines be affected differently by seeing their HSP60 epitopes presented by activated T cells compared to recognizing HSP60 presented by classical APC? To study this possibility, we incubated the Anti-p277 line for 3 days with either irradiated APC and p277 peptide or with irradiated, activated A2b T cells. The Anti-p277 T cells were then recovered from the cultures, maintained for 4 additional days in culture without APC or A2b T cells, and then stimulated with APC and p277 peptide, with mitogenic Con A or immobilized anti-TCR. Figure 8 presents the outcome. It can be seen that the Anti-p277 T cells, following co-culture with APC and p277 could still respond to a second stimulation with APC and p277 or with mitogenic αTCR or ConA; however, previously co-culturing the anti-p277 line with activated A2b T cells rendered the Anti-p277 line anergic; the line now failed to proliferate in response to APC and p277 or to either of the two mitogens (Figure 8A). The Anti-p277 T cells could still secrete IFNγ (Figure 8B) but not TGFβ1, IL-10 or IL-4, despite their failure to proliferate. The Anti-p277 line cells, however, went on to die in vitro after their exposure to the activated A2b T cells. Thus, it appears that the interaction of anti-ergotypic T-cell lines with their target activated effector T cells leads to anergy and loss of the anti-ergotypic T cells; activated effector T cells and regulator T cells can down-regulate each other. In contrast, anti-ergotypic T cells can be maintained in culture by APC and specific peptide antigen [22].


HSP60 as a target of anti-ergotypic regulatory T cells.

Quintana FJ, Mimran A, Carmi P, Mor F, Cohen IR - PLoS ONE (2008)

Anti-ergotypic HSP60-specific T cells become anergic after interacting with activated T cells.Anti-ergotypic Anti-p277 T cells were stimulated for 3 days with irradiated, activated A2b cells (A2b) or with irradiated APC fed with the p277 peptide (APC). The Anti-p277 T cells were maintained for 4 additional days in culture, and stimulated with APC and p277 peptide, Con A or immobilized anti-TCR (αTCR) antibodies. T-cell proliferation (A) and IFNγ (B) release were measured after 3 days. The proliferative responses are presented as the ΔCPM (±SEM) (A), and the IFNγ as pg/ml±SEM (B) of triplicate cultures. Three to five independent experiments produced similar results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2602852&req=5

pone-0004026-g008: Anti-ergotypic HSP60-specific T cells become anergic after interacting with activated T cells.Anti-ergotypic Anti-p277 T cells were stimulated for 3 days with irradiated, activated A2b cells (A2b) or with irradiated APC fed with the p277 peptide (APC). The Anti-p277 T cells were maintained for 4 additional days in culture, and stimulated with APC and p277 peptide, Con A or immobilized anti-TCR (αTCR) antibodies. T-cell proliferation (A) and IFNγ (B) release were measured after 3 days. The proliferative responses are presented as the ΔCPM (±SEM) (A), and the IFNγ as pg/ml±SEM (B) of triplicate cultures. Three to five independent experiments produced similar results.
Mentions: We have shown in the previous sections that HSP60-specific anti ergotypic T cells can recognize and down-regulate arthritogenic T cells, in vitro and in vivo. However, any regulatory mechanism has to be regulated; uncontrolled down-regulation of immunity would be as detrimental to the organism as uncontrolled autoimmunity [22]. We therefore studied whether the stimulation of HSP60-specific anti-erogotypic T cells by activated T cells might itself affect the regulators. In other words, might the anti-ergotypic HSP60-specific T-cell lines be affected differently by seeing their HSP60 epitopes presented by activated T cells compared to recognizing HSP60 presented by classical APC? To study this possibility, we incubated the Anti-p277 line for 3 days with either irradiated APC and p277 peptide or with irradiated, activated A2b T cells. The Anti-p277 T cells were then recovered from the cultures, maintained for 4 additional days in culture without APC or A2b T cells, and then stimulated with APC and p277 peptide, with mitogenic Con A or immobilized anti-TCR. Figure 8 presents the outcome. It can be seen that the Anti-p277 T cells, following co-culture with APC and p277 could still respond to a second stimulation with APC and p277 or with mitogenic αTCR or ConA; however, previously co-culturing the anti-p277 line with activated A2b T cells rendered the Anti-p277 line anergic; the line now failed to proliferate in response to APC and p277 or to either of the two mitogens (Figure 8A). The Anti-p277 T cells could still secrete IFNγ (Figure 8B) but not TGFβ1, IL-10 or IL-4, despite their failure to proliferate. The Anti-p277 line cells, however, went on to die in vitro after their exposure to the activated A2b T cells. Thus, it appears that the interaction of anti-ergotypic T-cell lines with their target activated effector T cells leads to anergy and loss of the anti-ergotypic T cells; activated effector T cells and regulator T cells can down-regulate each other. In contrast, anti-ergotypic T cells can be maintained in culture by APC and specific peptide antigen [22].

Bottom Line: Anti-ergotypic T cells responded to T-cell HSP60 by proliferation and secreted IFNgamma and TGFbeta1.In vivo, adoptive transfer of an anti-ergotypic HSP60-specific T-cell line led to decreased secretion of IFNgamma by arthritogenic T cells and ameliorated adjuvant arthritis (AA).Thus, by functioning as an ergotope, HSP60 can control both the effector T cells and the regulatory HSP60-specific T cells that control them.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel. fquintana@rics.bwh.harvard.edu

ABSTRACT
The 60 kDa heat shock protein (HSP60) has been reported to influence T-cell responses in two ways: as a ligand of toll-like receptor 2 signalling and as an antigen. Here we describe a new mechanism of T-cell immuno-regulation focused on HSP60: HSP60 is up-regulated and presented by activated T cells (HSP60 is an ergotope) to regulatory (anti-ergotypic) T cells. Presentation of HSP60 by activated T cells was found to be MHC-restricted and dependent on accessory molecules - CD28, CD80 and CD86. Anti-ergotypic T cells responded to T-cell HSP60 by proliferation and secreted IFNgamma and TGFbeta1. In vitro, the anti-ergotypic T cells inhibited IFNgamma production by their activated T-cell targets. In vivo, adoptive transfer of an anti-ergotypic HSP60-specific T-cell line led to decreased secretion of IFNgamma by arthritogenic T cells and ameliorated adjuvant arthritis (AA). Thus, the presentation of HSP60 by activated T cells turns them into targets for anti-ergotypic regulatory T cells specific for HSP60. However, the direct interaction between the anti-ergotypic T regulators (anti-HSP60) and the activated T cells also down-regulated the regulators. Thus, by functioning as an ergotope, HSP60 can control both the effector T cells and the regulatory HSP60-specific T cells that control them.

Show MeSH
Related in: MedlinePlus