Title

Regulatory role of B cells in the establishment of local inhalational tolerance in a murine model of asthma

Date of Completion

January 2009

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Mice sensitized to OVA and subjected to acute OVA aerosol exposures (3-10 days) develop allergic airway disease (AAD) characterized by Th2 cytokine-dependent pulmonary eosinophilia, methacholine hyperresponsiveness and antigen-specific IgE elevation. However, chronic continuous Ag exposure (42 days) results in resolution of AAD and the development of local inhalational tolerance (LIT). The establishment of LIT corresponds to an accumulation of CD4 T regulatory cells in the draining lymph nodes of the lung (HLN) along with a retention of B cells. We investigated the role of B cells in the resolution of AAD and the development of LIT. Adoptive transfer of HLN B cells from LIT mice to OVA-sensitized recipients resulted in attenuated AAD following subsequent OVA aerosol exposure, as determined by reduced BAL leukocytosis and eosinophilia, decreased tissue inflammation, and absent methacholine hyper-responsiveness. The protection transferred by LIT HLN B cells was Ag specific and was associated with accumulation of Foxp3+ T regulatory cells regionally in BAL and HLN, but not systemically. In vitro assessment demonstrated that the LIT HLN B cells exerted this regulatory effect via TGFβ induced conversion of CD4+ Foxp3- T effector cells into functionally suppressive CD4+ Foxp3+ T regulatory cells. The development of LIT coincided with the genesis of a unique B cell population within the LIT HLN B cells characterized by the up-regulation of the surface marker CD5. It could be postulated that this is a unique regulatory B cell population that contributes to the resolution of AAD and the development of LIT. ^