T cells have a critical role in regulating the protective immune response to Mycobacterium tuberculosis. As a result of studies supported by AI-27243, our understanding of the interaction between human T cells and macrophages in response to M. Tuberculosis has increased substantially during the last five years. First, M. Tuberculosis antigens activate three major T cell subsets from healthy tuberculin positive donors: V delta2 + gamma delta TCR bearing T cells (gamma delta T cells and CD8+ alpha beta (ab) TCR+ T cells (CD 8 T cells) in addition to CD4+ ab T cell receptor (TCR) bearing T cells (CD 4 T cells. Second, all three T cell subsets produce IFN-gamma and can serve as cytotoxic effector cells (CTL) against M. Tuberculosis infected macrophages, fitting into a Th-1 like pattern. These findings allow refinement of the model in which control of mycobacterial growth and maintenance of immunity requires the activation not only of CD4+ T cells and gamma delta T cells, but also of CD8+ T cells. This model postulates that there is a defined sequence of T cell subset recruitment and that the antigen processing mechanisms used by M. Tuberculosis infected mononuclear phagocytes are critical in the recruitment of T cell subsets and in determining the antigen repertoire recognized by CD4+, CD8+ and gamma delta T cells. In addition, the model postulates that both secretion of macrophage activating cytokines and CTL effector function are necessary for protective immune responses to M. Tuberculosis. There are three specific aims to test the postulates of this model: 1. To further characterize a 10-14KD M. tuberculosis antigen for V delta2+ gamma delta T cells, to determine if the antigen can be detected on the surface of mononuclear phagocytes for presentation to V delta2+ gamma delta T cells and to determine if gamma delta T cells activated by this antigen enhance the production by mononuclear phagocytes of chemokines (MIP-1alpha/beta, RANTES) and cytokines (IL-12, IL-15) that promote T cell recruitment and differentiation into CTL. 2. To characterize the antigen processing pathways of M. tuberculosis antigens for class II MHC presentation to CD4+ T cells, using the 30kD 85B antigen as model antigen. 3. To characterize the repertoire of antigens, the antigen-processing pathway and CTL function of CD8+ T cells reactive to M. tuberculosis in comparison to CD4+ and gamma delta T cells. These studies will provide insight into the regulation of human T cell subsets involved in protective immunity to M. tuberculosis, which is necessary for the design of improved vaccines, and immunotherapies for tuberculosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Shukla, Supriya; Richardson, Edward T; Drage, Michael G et al. (2018) Mycobacterium tuberculosis Lipoprotein and Lipoglycan Binding to Toll-Like Receptor 2 Correlates with Agonist Activity and Functional Outcomes. Infect Immun 86:
Athman, Jaffre J; Sande, Obondo J; Groft, Sarah G et al. (2017) Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation. J Immunol 198:2028-2037
Karim, Ahmad Faisal; Reba, Scott M; Li, Qing et al. (2017) Toll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function. Eur J Immunol 47:1513-1524
Karim, Ahmad F; Sande, Obondo J; Tomechko, Sara E et al. (2017) Proteomics and Network Analyses Reveal Inhibition of Akt-mTOR Signaling in CD4+ T Cells by Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan. Proteomics 17:
Li, Qing; Karim, Ahmad F; Ding, Xuedong et al. (2016) Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis. Sci Rep 6:27566
Sande, Obondo J; Karim, Ahmad F; Li, Qing et al. (2016) Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL. J Immunol 196:691-702
Athman, Jaffre J; Wang, Ying; McDonald, David J et al. (2015) Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages. J Immunol 195:1044-53
Richardson, Edward T; Shukla, Supriya; Sweet, David R et al. (2015) Toll-like receptor 2-dependent extracellular signal-regulated kinase signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect Immun 83:2242-54
Richardson, Edward T; Shukla, Supriya; Nagy, Nancy et al. (2015) ERK Signaling Is Essential for Macrophage Development. PLoS One 10:e0140064
Reba, Scott M; Li, Qing; Onwuzulike, Sophia et al. (2014) TLR2 engagement on CD4(+) T cells enhances effector functions and protective responses to Mycobacterium tuberculosis. Eur J Immunol 44:1410-21

Showing the most recent 10 out of 79 publications