B cells promote granulomatous inflammation during chronic Mycobacterium tuberculosis infection in mice

Author summaryMycobacterium tuberculosis remains a major public health threat worldwide. Balancing of the protective response and potentially tissue-damaging inflammation during tuberculous infection influences disease outcome. Chronic TB can be associated with lung-damaging inflammation, resulting in necrotization and cavity formation, pathological processes that are conducive to the transmission of M. tuberculosis. Restricting transmission is an important measure for TB control. We initiated experiments to characterize the role of B cells in modulating lung inflammation in chronic TB, the phase of infection during which tissue-damaging inflammation is most likely to occur. The results suggest that B cells can drive the development of lung inflammation in chronic TB by enhancing the levels of protective interferon (IFN)-gamma-producing CD4(+) T cells while restricting the expression of the immunosuppressive, anti-inflammatory IL-10. Thus, in chronic infection, B cells may contribute to optimal TB control but paradoxically promote lung pathology. Understanding how B cells regulate lung inflammation in TB may help the design of strategies that can reduce transmission, thereby achieving better TB control. The current study reveals that in chronic TB, the B cell-deficient mu MT strain, relative to wild-type (WT) C57BL/6 mice, displays in the lungs lower levels of inflammation that are associated with decreased CD4(+) T cell proliferation, diminished Th1 response, and enhanced levels of interleukin (IL)-10. The latter result raises the possibility that B cells may restrict lung expression of IL-10 in chronic TB. These observations are recapitulated in WT mice depleted for B cells using anti-CD20 antibodies. IL-10 receptor (IL-10R) blockade reverses the phenotypes of decreased inflammation and attenuated CD4(+) T cell responses in B cell-depleted mice. Together, these results suggest that in chronic murine TB, B cells, by virtue of their capacity to restrict expression of the anti-inflammatory and immunosuppressive IL-10 in the lungs, promote the development of a robust protective Th1 response, thereby optimizing anti-TB immunity. This vigorous Th1 immunity and restricted IL-10 expression may, however, allow the development of inflammation to a level that can be detrimental to the host. Indeed, decreased lung inflammation observed in chronically infected B cell-deficient mice, which exhibit augmented lung IL-10 levels, is associated with a survival advantage relative to WT animals. Collectively, the results reveal that in chronic murine TB, B cells play a role in modulating the protective Th1 immunity and the anti-inflammatory IL-10 response, which results in augmentation of lung inflammation that can be host-detrimental. Intriguingly, in tuberculous human lungs, conspicuous B cell aggregates are present in close proximity to tissue-damaging lesions manifesting necrosis and cavitation, suggesting the possibility that in human TB, B cells may contribute to the development of exacerbated pathology that is known to promote transmission. Since transmission is a major hindrance to TB control, investigating into whether B cells can shape the development of severe pulmonic pathological responses in tuberculous individuals is warranted.