Autoantigen-specific TGFbeta-induced Foxp3+ regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells.
Several strategies are being designed to test the therapeutic potential of Ag-specific regulatory T cells to prevent or treat autoimmune diseases. In this study, we demonstrate that naive CD4+ Foxp3- T cells specific for a naturally expressed autoantigen (H+/K+ ATPase) can be converted to Foxp3+ T regulatory cells (Tregs) when stimulated in presence of TGFbeta. TGFbeta-induced Tregs (iTregs) have all the characteristics of naturally generated regulatory T cells in vitro, and more importantly, are effective at preventing organ-specific autoimmunity in a murine model of autoimmune gastritis. H+/K+ ATPase specific iTregs were able to inhibit the initial priming and proliferation of autoreactive T cells, and appear to do so by acting on H+/K+ ATPase presenting dendritic cells (DC). DC exposed to iTregs in vivo were reduced in their ability to stimulate proliferation and cytokine production by H+/K+ ATPase specific T cells. iTregs specifically reduced CD80 and CD86 expression on the surface of H+/K+ ATPase presenting DC in vitro. These studies reveal the therapeutic potential of Ag specific iTregs to prevent autoimmunity, and provide a mechanism by which this population of regulatory T cells, and perhaps others, mediate their suppressive effects in vivo.
DiPaolo
Richard J
RJ
Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Brinster
Carine
C
Davidson
Todd S
TS
Andersson
John
J
Glass
Deborah
D
Shevach
Ethan M
EM
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005756:Gastritis / Q000276:immunology / Q000517:prevention & control; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009928:Organ Specificity; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D001324:Autoantigens; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta