Abstract

Our overall goal is to understand class II MHC(MHC-II) antigen processing mechanisms and how they may be modulated under different circumstances. In general terms, these studies will address: 1. Poorly understood aspects of the major MHC-II mechanisms. 2. Additional recently discovered processing mechanisms. 3. The means by which these various mechanisms are regulated under different pathophysiologic conditions, e.g. infection. The studies are relevent to understanding host-pathogen interactions (e.g with Mycobacterium tuberculosis), as well as mechanisms of vaccine efficacy (e.g with regard to targeting immunogens to specific antigen-processing pathways for enhancement of protective responses and understanding the mechanistic basis of adjuvant activity, cf NIH PA-97-101.
Aim 1. Characterization of distinct endocytic antigen processing mechanisms used for different epitopes and the relative roles of early endosomes and late endocytic compartments in these mechanisms. We will further explore mechanistic differences between late endocytic antigen processing mechanisms and an early endocytic processing pathway that was discovered in experiments funded by this grant during the previous funding period.
Aim 2. To characterize the mechanisms of phagocytic antigen processing. We will apply novel technological approaches to isolating and analyzing phagosomes for antigen processing function.
Aim 3. To determine the mechanisms by which Mycobacterium tuberculosis inhibits antigen processing. This may be of importance to understanding the maintainance of latent infection by this organism.
Aim 4. To characterize the mechanisms whereby cholera toxin (CT) and E. coli heat labile enterotoxin (LT) affect antigen processing. These toxins produce both inhibiting and enhancing effects at different stages of antigen processing and presentation. These studies will shed light on both antigen processing mechanisms and the effects of these adjuvants, which may be used in future human vaccines.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035726-07
Application #
6149792
Study Section
Immunobiology Study Section (IMB)
Program Officer
Deckhut Augustine, Alison M
Project Start
1994-05-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
7
Fiscal Year
2000
Total Cost
$274,721
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

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
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
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
Drage, Michael G; Tsai, Han-Chun; Pecora, Nicole D et al. (2010) Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nat Struct Mol Biol 17:1088-95
Ramachandra, Lakshmi; Qu, Yan; Wang, Ying et al. (2010) Mycobacterium tuberculosis synergizes with ATP to induce release of microvesicles and exosomes containing major histocompatibility complex class II molecules capable of antigen presentation. Infect Immun 78:5116-25
Simmons, Daimon P; Canaday, David H; Liu, Yi et al. (2010) Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN and class I MHC antigen cross processing by TLR9. J Immunol 185:2405-15
Reuter, Morgan A; Pecora, Nicole D; Harding, Clifford V et al. (2010) Mycobacterium tuberculosis promotes HIV trans-infection and suppresses major histocompatibility complex class II antigen processing by dendritic cells. J Virol 84:8549-60
Harding, Clifford V; Boom, W Henry (2010) Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat Rev Microbiol 8:296-307

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