How B cells shape the immune response against Mycobacterium tuberculosis
Maglione, Paul Joseph
MetadataShow full item record
Extensive work illustrating the importance of cellular immune mechanisms for protection against Mycobacterium tuberculosis has largely relegated B cell biology to an afterthought within tuberculosis (TB) host defense. However, recent studies have illuminated how B lymphocytes, through a variety of interactions with the cellular immune response, play previously underappreciated roles in host defense against intracellular pathogens. Consequently, we hypothesized that B cells and the humoral response influence host defense against M. tuberculosis by regulating cellular immunity.;Using flow cytometry and immunohistochemistry, we observed that B cells form profound pulmonary lymphoid aggregates during TB that express peanut agglutinin and GL7, two markers of germinal center B cells, in conjunction with CXCR5, a chemokine receptor that mediates the organization of B cells in lymphoid follicles. Further demonstrating characteristics of lymphoid tissue B cells, these pulmonary lymphocytes migrate in response to the lymphoid-associated chemokine CXCL13. We found that B cells both enhance mycobacterial containment and limit resultant immunopathology. Adoptive transfer of B cells complements the phenotypes of B cell-deficient mice without local residence of the transferred lymphocytes in the lungs, demonstrating that B cells mediate protective effects in an endocrine manner.;Fcgamma receptors regulate immunity by engaging immunoglobulins produced by B cells. C57BL/6 mice deficient in the inhibitory Fcgamma receptor, FcgammaRIIB, manifested enhanced mycobacterial containment and diminished immunopathology. These findings corresponded with increased IFN-gamma-producing CD4+ T cells as well as elevated expression of MHC II and B7 co-stimulatory molecules in the lungs. Upon M. tuberculosis infection and immune complex engagement, RIIB -/- macrophages produced more Th1-promoting IL-12p40. These data strongly suggest that FcgammaRIIB engagement can dampen the TB Th1 response by attenuating IL-12 production and/or activation of antigen presenting cells. Conversely, C57BL/6 mice lacking the gamma-chain shared by activating Fcgamma receptors had enhanced susceptibility and exacerbated immunopathology upon M. tuberculosis challenge, associated with increased production of the immunosuppressive cytokine IL-10. Thus, engagement of distinct Fcgamma receptors can divergently affect cytokine production and susceptibility during M. tuberculosis infection. Altering the endocrine immune regulation mediated by antibodies and Fcgamma receptors may provide novel means of enhancing immunity against M. tuberculosis..
- Theses and Dissertations