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PMID: 20037585 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms.

Nature immunology ·Vol. 11 ·No. 2 ·2010-02-00 ·Pages 129-35

Ise W, Kohyama M, Nutsch KM, Lee HM, Suri A, Unanue ER, Murphy TL, Murphy KM

Abstract

The inhibitory immunoregulatory receptor CTLA-4 is critical in maintaining self-tolerance, but the mechanisms of its actions have remained controversial. Here we examined the antigen specificity of tissue-infiltrating CD4(+) T cells in Ctla4(-/-) mice. After adoptive transfer, T cells isolated from tissues of Ctla4(-/-) mice showed T cell antigen receptor (TCR)-dependent accumulation in the tissues from which they were derived, which suggested reactivity to tissue-specific antigens. We identified the pancreas-specific enzyme PDIA2 as an autoantigen in Ctla4(-/-) mice. CTLA-4 expressed either on PDIA2-specific effector cells or on regulatory T cells was sufficient to control tissue destruction mediated by PDIA2-specific T cells. Our results demonstrate that both cell-intrinsic and non-cell-autonomous actions of CTLA-4 operate to maintain T cell tolerance to a self antigen.

MeSH Terms
Adoptive Transfer Animals Antigens, CD/immunology Autoantigens/immunology CTLA-4 Antigen Flow Cytometry Lymphocyte Activation/immunology Mice Mice, Transgenic Protein Disulfide-Isomerases/immunology Receptors, Antigen, T-Cell/immunology Self Tolerance/immunology T-Lymphocyte Subsets/immunology
Chemicals
Antigens, CD Autoantigens CTLA-4 Antigen CTLA4 protein, human Ctla4 protein, mouse Receptors, Antigen, T-Cell PDIA2 protein, human Protein Disulfide-Isomerases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Ise Wataru
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Kohyama Masako
Nutsch Katherine M
Lee Hyang Mi
Suri Anish
Unanue Emil R
Murphy Theresa L
Murphy Kenneth M
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1835
Published
2010-02-00
Epub
2009-00-27
Pages
129-35
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3235641
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NIAID NIH HHS · AI031238 · United States
NIAID NIH HHS · AI070489 · United States
External Links
PubMed source DOI: 10.1038/ni.1835 PMC Full Text View journal details
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