CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms.
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.
Ise
Wataru
W
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Kohyama
Masako
M
Nutsch
Katherine M
KM
Lee
Hyang Mi
HM
Suri
Anish
A
Unanue
Emil R
ER
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D019704:Protein Disulfide-Isomerases / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D015703:Antigens, CD; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D011948:Receptors, Antigen, T-Cell; C526504:PDIA2 protein, human; D019704:Protein Disulfide-Isomerases