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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
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
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
Gabrilovich, M I; Walrath, J; van Lunteren, J et al. (2013) Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis. Clin Exp Immunol 173:512-22
Hardy, Gareth A D; Sieg, Scott; Rodriguez, Benigno et al. (2013) Interferon-* is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers. PLoS One 8:e56527
Li, Qing; Ding, Xuedong; Thomas, Jeremy J et al. (2012) Rv2468c, a novel Mycobacterium tuberculosis protein that costimulates human CD4+ T cells through VLA-5. J Leukoc Biol 91:311-20
Simmons, Daimon P; Wearsch, Pamela A; Canaday, David H et al. (2012) Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing. J Immunol 188:3116-26
Liu, Yi C; Simmons, Daimon P; Li, Xiaoxia et al. (2012) TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9. J Immunol 188:1019-26
Mahon, Robert N; Sande, Obondo J; Rojas, Roxana E et al. (2012) Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cell Immunol 275:98-105
Lancioni, Christina L; Li, Qing; Thomas, Jeremy J et al. (2011) Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4(+) T cell activation via Toll-like receptors 1 and 2. Infect Immun 79:663-73

Showing the most recent 10 out of 82 publications