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Negative selection during the peripheral immune response to antigen.

Anderton SM, Radu CG, Lowrey PA, Ward ES, Wraith DC - J. Exp. Med. (2001)

Bottom Line: In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development.Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold.This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom. steve.anderton@ed.ac.uk

ABSTRACT
Thymic selection depends on positive and negative selective mechanisms based on the avidity of T cell interaction with antigen-major histocompatibility complex complexes. However, peripheral mechanisms for the recruitment and clonal expansion of the responding T cell repertoire remain obscure. Here we provide evidence for an avidity-based model of peripheral T cell clonal expansion in response to antigenic challenge. We have used the encephalitogenic, H-2 A(u)-restricted, acetylated NH(2)-terminal nonameric peptide (Ac1-9) epitope from myelin basic protein as our model antigen. Peptide analogues were generated that varied in antigenic strength (as assessed by in vitro assay) based on differences in their binding affinity for A(u). In vivo, these analogues elicited distinct repertoires of T cells that displayed marked differences in antigen sensitivity. Immunization with the weakest (wild-type) antigen expanded the high affinity T cells required to induce encephalomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development. Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.

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Tuning of T cell responsiveness is evident at the primed lymph node level. PLNCs were isolated from B10.PL×SJL mice immunized with either the 4Lys or 4Tyr peptides. PLNCs were tested for proliferative responses to dose ranges of each peptide. Data are from one of three experiments which gave consistent results.
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Figure 4: Tuning of T cell responsiveness is evident at the primed lymph node level. PLNCs were isolated from B10.PL×SJL mice immunized with either the 4Lys or 4Tyr peptides. PLNCs were tested for proliferative responses to dose ranges of each peptide. Data are from one of three experiments which gave consistent results.

Mentions: We then addressed the question of whether tuning of the cell lines had occurred in vivo or was a result of repeated in vitro stimulation with antigen. T cell hybridomas generated directly from PLNC populations were tested for response patterns to the priming antigen and wild-type peptide (Table ). Again we observed that hybridomas from mice primed with superagonists were increasingly insensitive to 4Lys and responded to the priming antigen at concentrations generally within the 1–100 nM range. Furthermore, analysis of proliferative responses of PLNC from mice immunized with either 4Lys or 4Tyr showed evidence of tuning (Fig. 4). Although the 4Tyr peptide behaved as a superagonist after priming with 4Lys, the response after priming with 4Tyr was equivalent to that seen to 4Lys after priming with 4Lys. From these data we conclude that the tuning event occurred during the development of immunity in vivo and was not the result of continued exposure to antigen in vitro.


Negative selection during the peripheral immune response to antigen.

Anderton SM, Radu CG, Lowrey PA, Ward ES, Wraith DC - J. Exp. Med. (2001)

Tuning of T cell responsiveness is evident at the primed lymph node level. PLNCs were isolated from B10.PL×SJL mice immunized with either the 4Lys or 4Tyr peptides. PLNCs were tested for proliferative responses to dose ranges of each peptide. Data are from one of three experiments which gave consistent results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195878&req=5

Figure 4: Tuning of T cell responsiveness is evident at the primed lymph node level. PLNCs were isolated from B10.PL×SJL mice immunized with either the 4Lys or 4Tyr peptides. PLNCs were tested for proliferative responses to dose ranges of each peptide. Data are from one of three experiments which gave consistent results.
Mentions: We then addressed the question of whether tuning of the cell lines had occurred in vivo or was a result of repeated in vitro stimulation with antigen. T cell hybridomas generated directly from PLNC populations were tested for response patterns to the priming antigen and wild-type peptide (Table ). Again we observed that hybridomas from mice primed with superagonists were increasingly insensitive to 4Lys and responded to the priming antigen at concentrations generally within the 1–100 nM range. Furthermore, analysis of proliferative responses of PLNC from mice immunized with either 4Lys or 4Tyr showed evidence of tuning (Fig. 4). Although the 4Tyr peptide behaved as a superagonist after priming with 4Lys, the response after priming with 4Tyr was equivalent to that seen to 4Lys after priming with 4Lys. From these data we conclude that the tuning event occurred during the development of immunity in vivo and was not the result of continued exposure to antigen in vitro.

Bottom Line: In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development.Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold.This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom. steve.anderton@ed.ac.uk

ABSTRACT
Thymic selection depends on positive and negative selective mechanisms based on the avidity of T cell interaction with antigen-major histocompatibility complex complexes. However, peripheral mechanisms for the recruitment and clonal expansion of the responding T cell repertoire remain obscure. Here we provide evidence for an avidity-based model of peripheral T cell clonal expansion in response to antigenic challenge. We have used the encephalitogenic, H-2 A(u)-restricted, acetylated NH(2)-terminal nonameric peptide (Ac1-9) epitope from myelin basic protein as our model antigen. Peptide analogues were generated that varied in antigenic strength (as assessed by in vitro assay) based on differences in their binding affinity for A(u). In vivo, these analogues elicited distinct repertoires of T cells that displayed marked differences in antigen sensitivity. Immunization with the weakest (wild-type) antigen expanded the high affinity T cells required to induce encephalomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development. Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.

Show MeSH
Related in: MedlinePlus