CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization (1)
Antagonizing CTLA-4 signaling enhances T cell proliferation, whereas cross-linking of CTLA-4 in vitro inhibits anti-CD3-induced T cell proliferation.
Oral exposure to PPE was performed by intragastric dosing of 6 mg of roasted PPE on 3 consecutive days, followed by weekly dosing of 6 mg of PPE (4 wks). CT (10 ug) was coadministered on days 1, 2, 3, 8, 15, and 21. Equivalent groups were additionally injected i.p. with 100 ug of anti-CTLA-4 mAb on days 1, 3, 7, 14, and 20 during the oral-dosing regime.
The group receiving 4 wks of oral treatment with PPE plus CT showed PPE-specific serum IgG1, IgG2a, and IgE. Blockade of CTLA-4 during the oral sensitization protocol increased both Th2-related (IgG1 and IgE) and Th1-related (IgG2a) PPE-specific Ab levels compared with PPE plus CT treatment group. The group that was exposed to PPE without CT produced low levels of PPE-specific IgG1 and IgG2a and no IgE.
Mice treated with anti-CTLA-4 without oral dosing of PPE showed a similar significant elevation of total IgE serum levels compared with control mice that received no treatment at all.
Blockade of CTLA-4 in this group resulted in a profound increase of allergen-specific IgE levels with the highest responses against Ara h 1, followed by Ara h 3 and Ara h 6.
Anti-CTLA-4 treatment induced higher base levels of serum mmcp-1 before oral challenge. Blockade of CTLA-4 only induced an increase in mmcp-1 serum concentration after oral challenge in the PPE plus CT treatment group, with mmcp-1 levels being four times higher than in the PPE plus CT treatment group.
Treatment with anti- CTLA-4 significantly enhanced Th2-associated (IL-4 and IL-5) and T regulatory (Tr)-related (IL-10) cytokine production in both MLN and spleen independent of PPE or CT administration.
Coadministration of the adjuvant CT significantly elevated IFN-g levels com- pared with levels in the non-CT-exposed groups.
CTLA-4 is also expressed on B cells, and CTLA-4 signaling on these cells has been shown to inhibit IL-4-driven isotype switching, thereby possibly preventing allergen-specific IgG1 and IgE production. CT is thought to stimulate Th2- dependent immune responses to a bystander Ag by provoking Th2 cytokine production. CT itself promotes dendritic cell activation and migration, which facilitates Ag presentation to the immune system. The CTLA-4 ligands CD80 and CD86 are expressed on mast cells.