Antigen-Specific Effector CD4 T Lymphocytes School Lamina Propria Dendritic Cells To Transfer Innate Tolerance

Abstract

Dendritic cells (DCs) have been shown to play a major role in oral tolerance and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive T regulatory cells. Herein, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-MOG carrying the myelin oligodendrocyte glycoprotein (MOG)35–55 epitope was orally administered into either T cell sufficient or deficient mice, only the T cell sufficient hosts yielded CD8α+ and CD8α− LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs up-regulated programmed cell death ligand 1 (PD-L1) during the initial interaction with MOG-specific T cells and utilized this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental allergic encephalomyelitis (EAE) induced with central nervous system (CNS) homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity.

IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis

“…The onset of EAE in C57BL/6 mice induced for disease with 300 μg MOGp usually manifests around day 10 post-immunization (23). However, when a similar disease induction regimen was applied to 13R -/- mice, the clinical signs of paralysis manifested as early as day 6 post-immunization while 13R +/+ control mice had disease onset around day 10 as is typical in our mouse colony (Fig.…”

“…MOG peptide (MOGp) encompassing aa residues 35-55 of MOG which is encephalitogenic in C57BL/6 mice (23) was purchased from EZBiolab (Westfield, IN). I-A b tetramer containing MOG aa 38-49 (MOG tet ) was obtained from NIH Core Tetramer Facillity (Emory University, Atlanta, Georgia).…”

“…EAE was induced with MOGp as described (23, 24). Briefly, female mice (6–8 week-old) were induced for EAE by s.c. injection of a 200μl IFA/PBS (v/v) solution containing 300μg, 100 μg, or 60μg MOG peptide and 200 μg of Mycobacterium tuberculosis H37Ra (Difco) in the footpads and at the base of the limbs.…”

Oral Tolerance Induction to Newly Introduced Allergen is Favored by a Transforming Growth Factor-β-Enriched Formula

“…The animal study protocol (VD2153.2) was approved by the Service Vétérinaire du Canton de Vaud, Switzerland (Figure 1A). The C57BL/6J CRL mice strain was chosen because it has been successfully used in OVA-induced food allergy and oral tolerance models [32,33,34,35,36]. Briefly, 5-week-old C57BL/6J CRL female mice (Charles River Laboratories, Lyon, France) were sensitized using two subcutaneous injections of 100 µg (Sigma) and 1 mg aluminum hydroxide (Sigma) in 50 µL of phosphate buffer saline (PBS; Sigma) on two separate sites (neck and back) at days 13 and 26.…”

In trans T cell tolerance exacerbates experimental allergic encephalomyelitis by interfering with protective antibody responses

“…In previous studies, we have shown that Ig-MOG and Ig-PLP1 are effective against EAE induced by MOG and PLP1 peptide, respectively (Cascio et al, 2013, Divekar, Haymaker, 2011, Legge et al, 2001, Legge, Gregg, 2002, Legge, Min, 2000). Also, both chimeras were able to display bystander suppression and modulate CNS homogenate-induced EAE which involves multiple epitopes and diverse T cell specificities.…”