The goal of this proposal is to characterize the mechanisms by which B cells contribute to the development of optimal anti-tuberculosis (TB) immunity. The importance of T cell immune response to Mycobacterium tuberculosis (Mtb) has been well established. The role of B cells in TB is not clearly defined. We and others have shown that B cells are a significant component of lung tuberculous granulomas in human and mice. They form conspicuous aggregates with features of germinal center B cells. Using the B cell-deficient mMT mouse, in conjunction with B cell transfer studies, we showed that B cells contribute significantly to anti-Mtb responses and are required for the optimal control of TB. Mice deficient in the inhibitory Fcg receptor IIB (FcgRIIB), relative to wildtype (WT) animals, exhibit an enhanced Th1 response in acute TB. The CD4+ T cells response of mMT mice is also altered in chronic infection. Together, these results provide strong evidence that B cells can regulate T cell immunity in TB, perhaps in part via FcgR engagement with antigen (Ag)-antibody (Ab) complex. We recently observed that BCG vaccination induces a Th1 response in mMT mice that is inferior to that observed in WT's. A recent study reports on the inability of BCG to optimally protect the CBA/xid mouse, another B cell-deficient strain. These BCG studies, together with published data that B cells can regulate T cell memory and secondary response to pathogen challenge, suggests that B cells contribute to vaccine efficacy. To stringently test the significance of B cells in regulating host immunity against Mtb, we initiated studies to examine the B cell response in a cynomolgus macaque (non-human primate; NHP) model, one that arguably most genuinely represents the human system. This study revealed that in the lungs of tuberculous NHP, as in human and mice, B cells can form discreet nodules and display enhanced expression of activation markers. We propose to use both murine and NHP TB models to rigorously test the hypotheses that: i) Specific functions of B cells contribute significantly to the host immune response to Mtb; ii) B cells are required for the development of effective T cell response in TB, including the CD4 T cell memory response; iii) B cells are essential for the development of optimal vaccine-engendered protection; and iv) Ag-Ab complex and FcgR can be exploited to enhance the host immune response to Mtb. We believe the proposed studies can shed light on the mechanisms by which B cells shape the host immune response to Mtb and lead to novel measures for harnessing humoral immunity to augment anti-TB immunity. PUBLIC HEALTH RELEVANCE: This grant proposal is designed to study the role of B cells in the development of effective immune response to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). It has been estimated that one- third of the world's population is infected with Mtb. This pathogen causes 2 million deaths each year globally. The HIV epidemic has made control of Mtb particularly difficult due to the increased susceptibility to TB of persons infected with HIV. This difficulty is further enhanced by emergence of extensively drug resistant Mtb strains that are remarkably difficult to treat. One highly efficient and cost-effective way to control TB is the development of a vaccine with high potency. BCG, the only TB vaccine in use, does not protect consistently. Requisite to the production of an effective anti-TB vaccine is knowledge concerning the host immune response to Mtb. This knowledge will also help in the development of novel treatment strategies against Mtb. While the importance of T cell immune response to Mtb has been well established, the role of B cells in TB is not clearly defined. We have observed that B cells are required for the development of optimal host immune response to Mtb, including those after BCG vaccination. Therefore, we propose to test the hypothesis that B cells contribute significantly to the development of optimal immune response to Mtb, and through the process, elucidate the mechanisms by which B cells engender protection against this infection. We believe the proposed studies can shed light on the mechanisms by which B cells shape the host immune response to Mtb. These mechanisms should reveal novel measures for harnessing humoral immunity to augment anti-TB host response, which can lead to the design of effective treatment for and prevention of TB.