Ovalbumin-protein sigma 1 M-cell targeting facilitates oral tolerance with reduction of antigen-specific CD4+ T cells.
OBJECTIVE
The follicle-associated epithelium (FAE) plays key roles in antigen uptake and subsequent induction of mucosal immunity. In this study, we examined whether M-cell targeting using a protein antigen (Ag) delivery system would induce oral tolerance instead of enhancement of Ag-specific mucosal antibody (Ab) responses.


METHODS
Mice were fed different doses of a recombinant protein sigma 1 of reovirus genetically conjugated to ovalbumin (OVA-psigma1), psigma1 only, or phosphate-buffered saline (PBS) before oral challenge with OVA plus cholera toxin as mucosal adjuvant. OVA-specific Ab and CD4-positive (CD4(+)) T-cell responses were determined.


RESULTS
A low dose of OVA-psigma1 reduced anti-OVA Ab and CD4(+) T-cell responses in both mucosal and systemic lymphoid tissues. OVA/MHC I-A(d) tetramer staining showed that the numbers of OVA-specific CD4(+) T cells were significantly reduced in lamina propria of mice fed OVA-psigma1 than those fed psigma1 only or PBS only. In fact, Foxp3 expressing CD25(+) CD4(+) T cells were markedly increased in this tissue. Nonetheless, CD25(+) CD4(+) T cells from the spleen, mesenteric lymph nodes, and Peyer's patches of orally tolerized mice showed increased transforming growth factor beta1 (TGF-beta1) and interleukin-10 (IL-10) production compared with nontolerized mice.


CONCLUSIONS
These results show that an FAE M-cell targeting protein Ag delivery system facilitates oral tolerance induction because of a reduction in Ag-specific CD4(+) T cells and increased levels of TGF-beta1 and IL-10 producing, CD25(+) CD4(+) regulatory T cells in both systemic and mucosal lymphoid tissues.
Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
Hideaki
H
Suzuki
Shinichi
S
Sekine
Kosuke
K
Kataoka
David W
DW
Pascual
Massimo
M
Maddaloni
Ryoki
R
Kobayashi
Keiko
K
Fujihashi
Haruo
H
Kozono
Jerry R
JR
McGhee
Kohtaro
K
Fujihashi
D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology*; D000939:Epitopes; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007114:Immunization; D007371:Interferon-gamma / Q000032:analysis; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009061:Mouth Mucosa / Q000166:cytology / Q000276:immunology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000032:analysis
D036022:Capsid Proteins; D000939:Epitopes; D053773:Transforming Growth Factor beta1; C031728:sigma 1 protein, reovirus; D007371:Interferon-gamma; D010047:Ovalbumin