This application for a mentored scientist award (KO-8) seeks 5 years of funding for research training in the cellular immunology and cell biology of M. tuberculosis infection for David H. Canaday, M.D. Research training will be provided by W. Henry Boom, M.D. and Clifford V. Harding, M.D.-Ph.D. in the Division of Infectious Diseases and the Department of Medicine at Case Western Reserve University. The research proposal which will provide the focus for Dr. Canaday's training is outlined below. M. tuberculosis is spread from person to person by inhalation of aerosolized mycobacteria. Most healthy people do not develop clinical tuberculosis. Instead, cellular immune responses become activated and are able to successfully control the active infection. T cells play a crucial role in regulating the cellular immune response. T cell subsets(CD4+, CD8+, gammadelta+), are activated by mycobacterial antigens, yet little is known about the roles and function of the different T cell subsets in the protective immune response to M. tuberculosis. While CD4+ T cells have been the focus of many studies, CD8+ T cells are an important accessory T cell subset in the protective immune response to M. tuberculosis. Recent studies by us and others have demonstrated that human CD8+ T cells serve as CTL for M. tuberculosis infected macrophages, produce IFN-gamma and are activated by mycobacterial antigens. The broad goal of the current studies is to determine the repertoire of mycobacterial proteins which stimulate human CD8+ T cells, to examine the antigen processing mechanism the macrophages use to present M. tuberculosis antigens on MHC class I molecules, and to determine the function of CD8+ T cells in patients with active tuberculosis.
The Aims are:
Aim 1. To determine the mycobacterial proteins and peptides recognized by human alphabeta TCR+ CD8+ T cells.
Aim 2. To determine the mechanism(s) used by M. tuberculosis infected macrophages to process and present mycobacterial proteins by MHC class I molecules.
Aim 3. To characterize the functional CD8+ T cell responses to specific proteins and peptides from in patients with active M. tuberculosis infection.
|Jones, Leola; McDonald, David; Canaday, David H (2007) Rapid MHC-II antigen presentation of HIV type 1 by human dendritic cells. AIDS Res Hum Retroviruses 23:812-6|
|Tobian, Aaron A R; Harding, Clifford V; Canaday, David H (2005) Mycobacterium tuberculosis heat shock fusion protein enhances class I MHC cross-processing and -presentation by B lymphocytes. J Immunol 174:5209-14|
|Tobian, Aaron A R; Canaday, David H; Boom, W Henry et al. (2004) Bacterial heat shock proteins promote CD91-dependent class I MHC cross-presentation of chaperoned peptide to CD8+ T cells by cytosolic mechanisms in dendritic cells versus vacuolar mechanisms in macrophages. J Immunol 172:5277-86|
|Pai, Rish K; Pennini, Meghan E; Tobian, Aaron A R et al. (2004) Prolonged toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages. Infect Immun 72:6603-14|
|Tobian, Aaron A R; Canaday, David H; Harding, Clifford V (2004) Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells. J Immunol 173:5130-7|
|Canaday, David H; Gehring, Adam; Leonard, Ethan G et al. (2003) T-cell hybridomas from HLA-transgenic mice as tools for analysis of human antigen processing. J Immunol Methods 281:129-42|
|Leonard, Ethan G; Canaday, David H; Harding, Clifford V et al. (2003) Antigen processing of the heptavalent pneumococcal conjugate vaccine carrier protein CRM(197) differs depending on the serotype of the attached polysaccharide. Infect Immun 71:4186-9|
|Canaday, David H; Beigi, Reza; Silver, Richard F et al. (2002) ATP and control of intracellular growth of mycobacteria by T cells. Infect Immun 70:6456-9|
|Brill, K J; Li, Q; Larkin, R et al. (2001) Human natural killer cells mediate killing of intracellular Mycobacterium tuberculosis H37Rv via granule-independent mechanisms. Infect Immun 69:1755-65|
|Canaday, D H; Wilkinson, R J; Li, Q et al. (2001) CD4(+) and CD8(+) T cells kill intracellular Mycobacterium tuberculosis by a perforin and Fas/Fas ligand-independent mechanism. J Immunol 167:2734-42|