Class I MHC Ag cross processing allows exogenous or vacuolar Ags to be processed for presentation to CD8+ T cells. Cross processing is essential for priming of CD8+ naive T cells by dendritic cells (DCs) in lymph nodes. A less recognized but potentially critical role of cross processing is to allow cells in non-lymphoid organs that are infected with vacuolar pathogens, e.g. Mycobacterium tuberculosis (MTB), to present pathogen-derived antigens to CD8+ effector T cells to elicit cytokine production or cytolytic function. DCs and macrophages may both harbor MTB and may hypothetically present MTB Ags to CD8+ effector T cells, allowing CD8+ T cells to contribute to containment of MTB infection. Research direction: This grant is to study basic mechanisms of bacterial Ag processing with a primary focus on MHC-I cross processing. MTB is selected as a model organism that represents an excellent model for processing of intravacuolar pathogens in addition to its significance as a human pathogen. Questions to be solved: We do not know which MTB-infected APCs have cross processing function;this has important implications for generation of immune responses vs. immune evasion. We do not understand mechanisms for cross processing of vacuolar pathogens, e.g. MTB, and cross processing functions of physiologically important lung APCs have not been investigated. Hypothesis: Cross processing of vacuolar organisms (e.g. MTB) allows recognition of infected cells by CD8+ T cells, contributing to host defense. DCs and macrophages may both cross present Ags to effector T cells, although they may use different cross processing mechanisms, undergo different regulation by pathogens, and play different roles in immune responses.
Aim 1 addresses basic mechanisms of cross processing of MTB.
Aim 2 investigates the cross processing functions of lung APCs.
Aim 3 addresses regulation of cross processing by Toll-like receptors, interferons and MTB. Significance in lay terms: These studies will discover mechanisms that allow immune recognition of the causative agent of tuberculosis by CD8+ T cells, which help fight tuberculosis infection. This will increase our understanding of tuberculosis pathogenesis and aid development of strategies for enhanced vaccine design or immunotherapy for tuberculosis and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034343-18
Application #
8265586
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
1994-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
18
Fiscal Year
2012
Total Cost
$384,689
Indirect Cost
$139,664
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
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
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
Nguyen, Thao P; Bazdar, Doug A; Mudd, Joseph C et al. (2015) Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling. J Leukoc Biol 97:1139-46
Richardson, Edward T; Shukla, Supriya; Nagy, Nancy et al. (2015) ERK Signaling Is Essential for Macrophage Development. PLoS One 10:e0140064
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
Xiao, Wenbin; Shameli, Afshin; Harding, Clifford V et al. (2014) Late stages of hematopoiesis and B cell lymphopoiesis are regulated by α-synuclein, a key player in Parkinson's disease. Immunobiology 219:836-44
Shukla, Supriya; Richardson, Edward T; Athman, Jaffre J et al. (2014) Mycobacterium tuberculosis lipoprotein LprG binds lipoarabinomannan and determines its cell envelope localization to control phagolysosomal fusion. PLoS Pathog 10:e1004471
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
Zhang, Lumin; Luo, Zhenwu; Sieg, Scott F et al. (2014) Plasmacytoid dendritic cells mediate synergistic effects of HIV and lipopolysaccharide on CD27+ IgD- memory B cell apoptosis. J Virol 88:11430-41

Showing the most recent 10 out of 90 publications