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Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity

Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity
Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity

Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3+ T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.

Autoimmunity, CD4 T cells, EAE, Fc engineering, FcRn, Tolerance
0896-8411
84-94
Challa, Dilip K.
433af413-17a0-4c55-b86f-21e4e5cedd6f
Mi, Wentao
35b74619-5f58-463b-9ff2-0544ddcba788
Lo, Su Tang
6c9e769f-7bd6-4e99-900e-1765383644ea
Ober, Raimund J.
31f4d47f-fb49-44f5-8ff6-87fc4aff3d36
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Challa, Dilip K.
433af413-17a0-4c55-b86f-21e4e5cedd6f
Mi, Wentao
35b74619-5f58-463b-9ff2-0544ddcba788
Lo, Su Tang
6c9e769f-7bd6-4e99-900e-1765383644ea
Ober, Raimund J.
31f4d47f-fb49-44f5-8ff6-87fc4aff3d36
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc

Challa, Dilip K., Mi, Wentao, Lo, Su Tang, Ober, Raimund J. and Ward, E. Sally (2016) Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity. Journal of Autoimmunity, 72, 84-94. (doi:10.1016/j.jaut.2016.05.007).

Record type: Article

Abstract

Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3+ T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.

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Accepted/In Press date: 11 May 2016
e-pub ahead of print date: 25 May 2016
Published date: 1 August 2016
Keywords: Autoimmunity, CD4 T cells, EAE, Fc engineering, FcRn, Tolerance

Identifiers

Local EPrints ID: 423671
URI: https://eprints.soton.ac.uk/id/eprint/423671
ISSN: 0896-8411
PURE UUID: 41fd63c6-c34e-433a-a78a-11f8cc1ab8c8
ORCID for Raimund J. Ober: ORCID iD orcid.org/0000-0002-1290-7430
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

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Date deposited: 27 Sep 2018 16:30
Last modified: 14 Mar 2019 01:21

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Contributors

Author: Dilip K. Challa
Author: Wentao Mi
Author: Su Tang Lo
Author: Raimund J. Ober ORCID iD
Author: E. Sally Ward ORCID iD

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