Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes-prone but not in diabetes-resistant mice.
The cholera toxin B subunit (CTB) has been used as adjuvant to improve oral vaccine delivery in type 1 diabetes. The effect of CTB/peptide formulations on Ag-specific CD4(+) T cells has remained largely unexplored. Here, using tetramer analysis, we investigated how oral delivery of CTB fused to two CD4(+) T-cell epitopes, the BDC-2.5 T-cell 2.5 mi mimotope and glutamic acid decarboxylase (GAD) 286-300, affected diabetogenic CD4(+) T cells in nonobese diabetic (NOD) mice. When administered i.p., CTB-2.5 mi activated 2.5 mi(+) T cells and following intragastric delivery generated Ag-specific Foxp3(+) Treg and Th2 cells. While 2.5 mi(+) and GAD-specific T cells were tolerized in diabetes-resistant NODxB6.Foxp3(EGFP) F1 and nonobese resistant (NOR) mice, this did not occur in NOD mice. This indicated that NOD mice had a recessive genetic resistance to induce oral tolerance to both CTB-fused epitopes. In contrast to NODxB6.Foxp3(EGFP) F1 mice, oral treatment in NOD mice lead to strong 2.5 mi(+) T-cell activation and the sequestration of these cells to the effector-memory pool. Oral treatment of NOD mice with CTB-2.5 mi failed to prevent diabetes. These findings underline the importance of investigating the effect of oral vaccine formulations on diabetogenic T cells as in selected cases they may have counterproductive consequences in human patients.
Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain; The Jackson Laboratory, Bar Harbor, ME, USA.
Maximiliano
M
Presa
Angela Zarama
AZ
Ortiz
Nahir
N
Garabatos
Cristina
C
Izquierdo
Elisa I
EI
Rivas
Luc
L
Teyton
Conchi
C
Mora
David
D
Serreze
Thomas
T
Stratmann
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology*; D022121:Cholera Vaccines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*
D000276:Adjuvants, Immunologic; D022121:Cholera Vaccines; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D002772:Cholera Toxin; D005968:Glutamate Decarboxylase
MHC tetramer; Oral vaccine; Type 1 diabetes