Class I MHC (MHC-I) molecules primarily present endogenous antigens, i.e. antigens that are present in the cytosol and are subject to the cytosolic processing mechanisms that comprise the conventional MHC-I processing pathway. However, exogenous antigens can also be presented by MHC-I molecules under certain circumstances, particularly in the case of particulate antigens. Recently, considerable attention has been focused on mechanisms that may contribute to alternate MHC-I processing pathways. Divergent results in several different systems have suggested that more than one alternate processing mechanism may exist. In some cases, MHC-I molecules present vacuolar antigens via alternate MHC-I processing mechanisms that are quite distinct from the conventional MHC- I processing pathway. These mechanisms may play important roles in generating CD8 T cell responses, especially to antigens expressed by vacuolar microorganisms and tumor cells. This project will define the mechanisms involved in the alternate MHC-I processing of several different types of exogenous antigens (intravacuolar bacteria and particulate vaccines). These studies may elucidate the basis of CD8 T cell responses to intravacuolar pathogens, such as Leishmania, Salmonella, and Toxoplasma species, and Mycobacterium tuberculosis. These studies also apply to tumor immunology and the role of alternate MHC-I processing mechanisms in the genesis of anti-tumor CD8 T cell responses. In addition, these studies will provide basic information that may be applied to develop strategies of therapeutic immunization to achieve protective CD8 T cell responses with non-viable vaccine preparations, in the absence of the endogenous antigen synthesis that is provided by live viral vaccine preparations. The use of non-viable particulate vaccines would be a safer way to elicit CD8 immunity in immunocompromised patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Allergy and Immunology Study Section (ALY)
Program Officer
Ridge, John P
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Case Western Reserve University
Schools of Medicine
United States
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Tashkandi, Hammad; Shameli, Afshin; Harding, Clifford V et al. (2018) Ultrastructural changes in peripheral blood leukocytes in ?-synuclein knockout mice. Blood Cells Mol Dis 73:33-37
Stefaniuk, Catherine M; Hong, Hong; Harding, Clifford V et al. (2018) ?-Synuclein concentration increases over time in plasma supernatant of single donor platelets. Eur J Haematol :
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 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:
Shameli, Afshin; Xiao, Wenbin; Zheng, Yan et al. (2016) A critical role for alpha-synuclein in development and function of T lymphocytes. Immunobiology 221:333-40
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
Nguyen, Thao P; Bazdar, Doug A; Mudd, Joseph C et al. (2015) Interferon-? inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling. J Leukoc Biol 97:1139-46
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

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