Journal
JOURNAL OF IMMUNOLOGY
Volume 180, Issue 8, Pages 5187-5200Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.180.8.5187
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Funding
- NCRR NIH HHS [P20 RR-020185, P20 RR020185, P20 RR020185-057149] Funding Source: Medline
- NIAID NIH HHS [R01 AI056286, R01 AI018958, AI-56286, R01 AI018958-23, R01 AI056286-03, AI-18958] Funding Source: Medline
- NIA NIH HHS [AG-25873, R01 AG025873, R01 AG025873-03] Funding Source: Medline
- NIDCR NIH HHS [R01 DE013812-05, R01 DE012242, R29 DE012242-05, R29 DE012242, DE-12242, DE-13812, R01 DE013812] Funding Source: Medline
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Mucosal tolerance induction generally requires multiple or large Ag doses. Because microfold (M) cells have been implicated as being important for mucosal tolerance induction and because reovirus attachment protein sigma 1 (p sigma 1) is capable of binding M cells, we postulated that targeting a model Ag to M cells via p sigma 1 could induce a state of unresponsiveness. Accordingly, a genetic fusion between OVA and the M cell ligand, reovirus p sigma 1, termed OVA-p sigma 1, was developed to enhance tolerogen uptake. When applied nasally, not parenterally, as little as a single dose of OVA-p sigma 1 failed to induce OVA-specific Abs even in the presence of adjuvant. Moreover, the mice remained unresponsive to peripheral OVA challenge, unlike mice given multiple nasal OVA doses that rendered them responsive to OVA. The observed unresponsiveness to OVA-p sigma 1 could be adoptively transferred using cervical lymph, node CD4(+) T cells, which failed to undergo proliferative or delayed-type hypersensitivity responses in recipients. To discern the cytokines responsible as a mechanism for this unresponsiveness, restimulation assays revealed increased production of regulatory cytokines, IL-4, IL-10, and TGF-beta 1, with greatly reduced IL-17 and IFN-gamma. The induced IL-10 was derived predominantly from FoxP3(+)CD25(+)CD4(+) T cells. No FoxP3(+)CD25(+)CD4(+) T cells were induced in OVA-p sigma 1-dosed IL-10-deficient (IL-10(-/-)) mice, and despite showing increased TGF-beta 1 synthesis, these mice were responsive to OVA. These data demonstrate the feasibility of using p sigma 1 as a mucosal delivery platform specifically for low-dose tolerance induction.
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