Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

Abstract

Under immunogenic conditions, both the site of initial Ag exposure and consequent T cell priming in specific draining lymph nodes (LNs) imprint the ensuing immune response with lasting tissue-selective tropism. With respect to immune tolerance, whether the site of tolerance induction leads to compartmentalized or, alternatively, pervasive tolerance has not been formally investigated. Using a murine model of inhalation tolerance, we investigated whether the induction of respiratory mucosal tolerance precludes the development of de novo Th2 sensitization upon subsequent exposure to the same Ag at distant mucosal (gut) and nonmucosal (cutaneous) sites. By tracking the proliferation of CFSE-labeled OVA-TCR transgenic CD4+ T cells upon OVA inhalation in vivo, we defined the site of tolerance induction to be restricted to the thoracic LNs. Expectedly, inhalation tolerance prevented de novo Th2 sensitization upon subsequent exposure to the same Ag at the same site. Importantly, although gut- and skin-draining LNs were not used during tolerance induction, de novo Ag-specific proliferation and Th2 differentiation in these LNs, as well as memory/effector Th2 responses in the gut (allergic diarrhea) and skin (late-phase cutaneous responses) were inhibited upon immunogenic challenge to the same Ag. Interestingly, this pervasive tolerogenic phenotype was not associated with the presence of suppressive activity throughout the lymphatics; indeed, potent suppressive activity was detected solely in the spleen. These data indicate that while inhalation tolerance is selectively induced in local thoracic LNs, its tolerogenic activity resides systemically and leads to pervasive immune tolerance in distant mucosal and nonmucosal sites.

Regulatory Role of B Cells in a Murine Model of Allergic Airway Disease

“…B cells have also been shown to regulate the Ag presenting function and maturation of dendritic cells (16), and the possibility of B cells from LIT HLN influencing Ag presentation during the course of our model remains to be investigated. The concept of B cells in regional LIT HLNs contributing to the regulation of AAD is consistent with the recent description that such local regulatory networks exist in draining lymph nodes and regulate inflammatory responses at adjacent mucosal sites (41). Similarly, the development of tolerance to intranasal administration of Ag is dependent on B cells in regional lymphoid tissue (42).…”

Restricted Aeroallergen Access to Airway Mucosal Dendritic Cells In Vivo Limits Allergen-Specific CD4+ T Cell Proliferation during the Induction of Inhalation Tolerance

“…A total of 1.25 3 10 3 washed BMDC were then added together with 1 3 10 5 purified CD4 + OVA-TCR transgenic T cells for 48 h, pulsed with [ T cell hyporesponsiveness in DLN and the airway mucosa that is mediated by a marked downregulation of allergen capture by AMDC subsets. These data are consistent with our and other studies showing induction of physiological and immunological tolerance after repeated exposure to innocuous allergens (11,13,16,38) and with a previous report that this process is dependent on the CCR7-guided migration of allergen-bearing DC to the DLN (18). We observed that inhaled aeroallergen is effectively captured by both CD11b hi and CD11b lo subsets of AMDC, equating to the CD103 2 and CD103 + DC subsets that have recently been described in both the lung and gut (3).…”

Intranasal Coadministration of Live Lactococci Producing Interleukin-12 and a Major Cow's Milk Allergen Inhibits Allergic Reaction in Mice

“…Indeed, previous studies have demonstrated that short-term or continuous intranasal exposure of mite allergen, but not of OVA, caused eosinophilia in BAL fluid and bronchoconstriction in BALB/c mice, along with elevated Th2-cell-associated production of antibodies in serum and Th2-cell-associated production of cytokines by splenocytes (28,49), whereas other studies have demonstrated that repeated exposure of BALB/c mice to an inhaled low dose of OVA inhibited the potential to develop a specific Th2 response in the periphery due to a noncompartmentalized induced immune tolerance (5,44). In a recent study, the prevention of a cellular and a humoral Th2-mediated allergic response was obtained by intranasal administration of three consecutive high doses of OVA (100 g), whereas lower doses (10 g) were found to be less effective and intranasal treatment was less effective than orally induced tolerance (29).…”