In humans, exposure to Mycobacterium tuberculosis (Mtb) results in varied infection and disease outcomes. 5- 10% of individuals infected with Mtb manifest disease, with evidence of infection in the remaining majority evinced only as positivity of IGRA (interferon gamma release assay). Given that the risk of developing reactivation TB is ~10% per lifetime in immunocompetent LTBI, it is thought the anti-TB immunity developed in this population can control the infection rather effectively. Another group, termed resisters, are defined as persons who remain IGRA-negative despite prolonged heavy exposure to Mtb. Resisters, compared to LTBI subjects, exhibit an interferon (IFN)γ-independent T cell response. The non-IFNγ T cell response to Mtb antigens (Ags), in conjunction with class switch recombination and the relatively high binding affinity Abs developed in resisters, suggests that this population has been infected with and has established an adaptive immune response to Mtb. Our Brazil household contact (HHCs) study of pulmonary TB showed differential IGRA response in the exposed HHCs despite having similar exposure to the infectious index case. Approximately 45% of HHCs were found to be IGRA negative. We defined the resister IGRA negative group as “Resistant to IGRA Conversion” (RIC) and the IGRA positive group as IGRA Converters (IC). Our preliminary data show that IFNγ-independent adaptive T cell immunity is engaged in RIC-HHCs and peripheral blood mononuclear cells from RIC-HHCs restrict Mtb growth. Further, preliminary data points to GM-CSF-secreting T cells as a likely component of the IFNγ-independent T cell response. GM-CSF signaling enhances IL-1β production and given that IL-1β is critical to anti-bacterial immunity in TB, we hypothesize that stable GM-CSF secreting memory T cells contribute to the RIC phenotype and the cytokine may also have a significant role in IC-HHCs. Accumulating evidence suggests that antibodies (Abs) play a role in regulating infection and disease outcomes in individuals exposed to Mtb, including the RIC- and IC-HHCs. We showed that Tfh cells (the CD4 T helper cell that is essential for the development of the B cell and Ab responses) from LTBI subjects harbor phenotypically distinct subsets that have been linked to discrepant B cell-regulatory functions in varied immunological systems. We thus posit that varied functions of Tfh cells in individuals exposed to Mtb may influence infection outcome by directing the development of distinct Ab responses. Comparative characterization of anti-TB immunity in RIC-HHCs versus IC-HHCs is a major goal of this proposal. The proposed studies will likely illuminate the IFNγ-independent T cell mediated immunological mechanisms that define the RIC phenotype, and of protective mechanisms mediated by the Tfh cell-B cell-Ab axis--this may lead to the development of novel vaccine targets. We will reconsent HHCs, retest them for their IGRA status and then recruit to the study the ones wh...