These mediators in turn stimulate the maturation of antigen presenting cells and initiation of adaptive immune responses such as the development and proliferation of antigen-specific effector T cell subsets. In the case of intracellular pathogens, effector T cells egress from lymph nodes and migrate to the site of infection where they activate infected macrophages via IFN-c. Some studies suggest PAMPs also enhance the function of effector T cells. M. tuberculosis stimulates PRRs through a number of TLR VE-822 ligands and other PAMPs. Studies in humans and mice have implicated TLR2, TLR9, and TLR signaling molecules in susceptibility to TB. Because of their immunomodulatory properties, PRR ligands are being exploited as adjuvants in vaccine formulations and as therapeutics for infectious, autoimmune, and neoplastic disorders. In this report we investigated whether in vitro immunomodulation of QFT-GIT with TLR agonists polyinosine-polycytidylic acid ; TLR3), lipopolysaccharide, and imiquimod can be used to enhance the response of T cells in individuals with LTBI. We also investigated the potential mechanisms through which TLR agonists modulate IGRA. In this report we describe a novel application for PRR agonists as in vitro immunomodulators of IGRA for diagnosis of latent M. tuberculosis infection. The findings from this study suggest that immunomodulation of IGRA with PRR ligands may be a useful strategy for addressing the shortcomings in the sensitivity of the commercially available whole blood IGRA. Although immunomodulation was shown to be effective in a small cohort of nfected subjects of Asian, Indian, and Caucasian ancestries, longitudinal studies with a larger number of participants and in more diverse populations are needed to determine the sensitivity and specificity of IGRA with immunomodulators at various cutoffs compared to the standard assay. Immunomodulation of IGRA may be particularly useful in the pediatric and immunocompromised populations where IGRAs have had lower sensitivities. It was recently shown that IFN-c response of T cells stimulated with M. tuberculosis whole cell lysate compared with purified secreted antigens better correlated with lower risk of subsequent HIV-associated TB. Given the abundance of potent PAMPs in the M. tuberculosis WCL, it would be interesting to determine whether immunomodulation of IGRA with PAMPs elicits an IFN-c response that better correlates with immunity to TB. In vitro immunomodulation may also have broader applications for sensitive diagnosis of infectious diseases and autoimmune disorders with T cell-mediated pathogenesis. Whether immunomodulation of IGRA is equally effective for eliciting a T cell response in subjects with active TB was not investigated in this study. It will be interesting to determine whether immunomodulators can overcome the functional impairment of ‘‘exhausted’’ T cells that occur during chronic infection. The modulation of T cell responses in IGRA by exogenous PAMPs raises the question whether endogenous signals modulate the output of IGRA and therefore account for the within-subject variability that has been often observed with IGRA. The heterogeneous T cell responses observed between and within subjects in this study suggest endogenous biological factors present in blood cooperate with exogenous TLR ligands to modulate IGRA. It was recently shown that the antimycobacterial activity of human monocyte-derived macrophages.