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Negative selection during the peripheral immune response to antigen

Negative selection during the peripheral immune response to antigen
Negative selection during the peripheral immune response to antigen

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 Au-restricted, acetylated NH2-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 Au. 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.

Apoptosis, Autoimmunity, Encephalomyelitis, Repertoire selection, T cells
0022-1007
1-11
Anderton, S. M.
fa3ef6ed-8ff8-455f-a7a3-98ce20f00fe9
Radu, C. G.
7b0cdea8-4ad8-4c89-89f7-eb6083504c1c
Lowrey, P. A.
42afc9db-94ff-4906-998f-7de4f2bb27a5
Ward, E. S.
b31c0877-8abe-485f-b800-244a9d3cd6cc
Wraith, D. C.
21518732-4596-4154-a875-e5767fe4f580
Anderton, S. M.
fa3ef6ed-8ff8-455f-a7a3-98ce20f00fe9
Radu, C. G.
7b0cdea8-4ad8-4c89-89f7-eb6083504c1c
Lowrey, P. A.
42afc9db-94ff-4906-998f-7de4f2bb27a5
Ward, E. S.
b31c0877-8abe-485f-b800-244a9d3cd6cc
Wraith, D. C.
21518732-4596-4154-a875-e5767fe4f580

Anderton, S. M., Radu, C. G., Lowrey, P. A., Ward, E. S. and Wraith, D. C. (2001) Negative selection during the peripheral immune response to antigen. The Journal of Experimental Medicine, 193 (1), 1-11. (doi:10.1084/jem.193.1.1).

Record type: Article

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 Au-restricted, acetylated NH2-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 Au. 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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More information

e-pub ahead of print date: 27 December 2000
Published date: 1 January 2001
Keywords: Apoptosis, Autoimmunity, Encephalomyelitis, Repertoire selection, T cells

Identifiers

Local EPrints ID: 425135
URI: https://eprints.soton.ac.uk/id/eprint/425135
ISSN: 0022-1007
PURE UUID: 4a158ede-e052-4fa8-99e9-8674563b65ff
ORCID for E. S. Ward: ORCID iD orcid.org/0000-0003-3232-7238

Catalogue record

Date deposited: 11 Oct 2018 16:30
Last modified: 07 Aug 2019 00:21

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Contributors

Author: S. M. Anderton
Author: C. G. Radu
Author: P. A. Lowrey
Author: E. S. Ward ORCID iD
Author: D. C. Wraith

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