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

Abstract

Mice sensitized to ovalbumin (OVA) develop a biphasic response to OVA aerosols, such that acute exposure results in allergic airway disease (AAD) while chronic exposure results in local inhalational tolerance (LIT), with resolution of local pulmonary responses but persistence of the systemic allergic response. We have previously reported that B cell lymphocytosis persists in hilar lymph nodes (HLN) during LIT and that CD4+CD25+Foxp3+ Treg cells are significantly increased in the HLN of LIT mice. This raised the consideration that B cells were involved in modulating the LIT response. Methods and Results: CD19+ B cells isolated from HLN of LIT mice were transferred to sensitized mice before inhaled antigen challenge. Compared to vehicle or AAD CD19+ transferred mice, LIT CD19+ transferred mice developed less BAL leukocytosis and eosinophilia (p < 0.05). In vivo, mice with attenuated AAD following LIT HLN B cell transfer showed a significant increase in the percentages of CD4+ Foxp3+ Treg cells in BAL and HLN, but not systemically (p < 0.03). This protection was antigen specific as LIT HLN B cells did not limit inflammation when transferred to bovine serum albumin (BSA) sensitized mice that were subsequently aerosolized with BSA. In vitro, LIT HLN B cells induced conversion of CD4+CD25‐ Teff cells to CD4+CD25+Foxp3+ T regulatory cells (Treg). The ability to induce suppressive Treg cells was regional, since B cells from AAD or systemic sites during LIT failed to do so. CFSE labeling of LIT HLN B cells demonstrated that these B cells home in and are retained at active sites of inflammation. Conclusions: These observations support a novel mechanism of regional immune regulation, possibly related to the development of a subset of regulatory B cells within the LIT HLN B cell population. This work was funded by NIH/AI R01 HL‐43573

Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice

“…These data were consistent with previous reports indicating that Bregs must be activated to be effective (19). Moreover, consistent with other Bregs (15,16,30,31), TIM-1 + Bregs were antigen specific, since TIM-1 + B cells from mice receiving an unrelated (C3H) allograft were unable to prolong graft survival when transferred into JHD recipients of B6 islets ( Figure 6B). Likewise, transfer of TIM-1 + B cells from BALB/c mice exposed to B6 alloantigen protected JHD recipients from rejecting B6 islets, but not C3H islets (Supplemental Figure 3A).…”

“…Bregs have previously been implicated in amelioration of allergic airway disease (31)(32)(33). Adoptive transfer of TIM-1 + , but not TIM-1 -, B cells from mice with OVA-induced local inhalational tolerance, markedly reduced OVA-induced allergic airway disease in JHD recipients, as determined by reduced BAL leukocytosis, tissue inflammation, and bronchiolar goblet cell hyperplasia (Supplemental Figure 4), thus confirming our results in an independent model.…”

Multiple Mechanisms of Immune Suppression by B Lymphocytes

“…Sublingual antigen challenge, a strategy for inducing oral tolerance, was partially impaired in B cell-deficient mice through a mechanism that depended on induction of FoxP3 + Tregs (113). In a separate study, repeated nasal antigenic challenge of mice induced a regulatory B-cell population in the local draining lymph node that suppressed lung inflammation and asthma in recipient ovalbumin (OVA)-sensitized mice after adoptive transfer (114). The effectiveness of these regulatory B cells was linked to B-cell expression of TGFβ but not IL-10 and the accumulation of FoxP3 + Tregs in the lung mucosa and local lymph nodes.…”

Regulatory T Cells Negatively Regulate Neovasculature of Airway Remodeling via DLL4-Notch Signaling

“…Previous studies using chronic allergen challenge models showed an expansion of Treg (44,45). The expansion includes actual proliferation of Treg in response to chronic Ag stimulation and also peripheral conversion of Teff to Treg under appropriate environmental cues, such as the presence of TGF-␤ and dendritic cell-derived retinoic acid, inhibited costimulation or IL-2 production, and the presence of subimmunogenic Ag conditions (46 -50).…”