Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity.
The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.
Schmidt
Emily M
EM
Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom.
Wang
Chun Jing
CJ
Ryan
Gemma A
GA
Clough
Louise E
LE
Qureshi
Omar S
OS
Goodall
Margaret
M
Abbas
Abul K
AK
Sharpe
Arlene H
AH
Sansom
David M
DM
Walker
Lucy S K
LS
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell