Role of TH2 Cytokines in Regulatory B Cell Biolog

B cells are now appreciated to be far more than antibody secreting cells. Throughout the last two decades B cells have been described to utilize a vast array of mechanisms to influence immune responses. Immune tolerance is achieved by a network of cells composed of regulatory T cells, tolerogenic DC and now regulatory B cells are held as a significant part of this network. However, much of the biology of regulatory B cells has yet to be uncovered. This thesis set out to understand how regulatory B cells may be modulated during T H2 responses in order gain insight into their dysregulation that may contribute to allergic disease.;To understand how regulatory B cells are modulated during allergic responses, we investigated the effects of TH2 cytokines (IL-5 and IL-4) on their regulatory function and growth in vitro. Previously, the lab reported that culture with CD40 ligand (CD40L) and interleukin 5 (IL-5) stimulated the secretion of IL-10 from murine B cells. In this thesis we further described this stimulation to induce IL-10 production specifically from B-1a cells which was inhibited in the presence of IL-4. The suppressive capacity of the IL-10 producing B cells was proven in vivo in an allergic airway disease model and found to be dependent on their secretion of IL-10. Adoptive transfer of CD40L and IL-5 stimulated B cells reduced airway resistance measured using plethysmography, and cellular infiltration and cytokines in the airways of sensitized mice. We suggest that regulatory B cell growth and function may be limited in the context of allergic inflammation due to the presence of IL-4 and may allow for the continuation of inappropriate responses to allergens. However, enhancing the number and function of these B cells could lead to reduced disease severity and potentially the induction of tolerance.;Similar in vitro cultures were performed with human B cells from the peripheral blood. Inhibitors were used to target signaling pathways downstream of CD40L and IL-5 stimulation to understand the necessary pathways for regulatory B cells growth and function in both mice and human B cells. Bruton's tyrosine kinase, nuclear factor of activated T cells, JAK, and STAT signaling may all play a part in regulating suppressive function and growth of IL-10 producing B cells.;Together this work provides insight into the modulation of regulatory B cells during allergic inflammation. We also identify possible targets to further investigate as therapeutics to enhance or inhibit regulatory B cell activity. Many protective and pathogen roles have been described for regulatory B cells spanning autoimmunity to infectious disease. While the focus of this thesis was in the context of allergic inflammation, modulation of regulatory B cells with the identified targets could be employed throughout human disease.