Project: Research project

Project Details


DESCRIPTION (Adapted from Investigator's Abstract): Recent studies have
identified the CD1 family of cell surface glycoproteins as novel antigen
presenting molecules encoded by genes located outside of the major
histocompatibility complex. Identification of naturally occurring antigens
presented by CD1 has revealed the surprising finding that these prominently
include a range of foreign lipids and glycolipids, such as several that are
known to exist in the cell walls and membranes of pathogenic mycobacteria.
Among the currently known CD1-presented antigens, the best structurally
characterized are the mycolic acids and their monoglucosylated analogue,
glucose monomycolate (GMM). These compounds have a lipid structure that is
unlike any found in mammalian tissues, and occur abundantly as a major outer
cell membrane component in a variety of pathogenic bacteria, including
Mycobacterium tuberculosis. Recognition of these lipids appears to be a
frequent feature of CD1b-restricted M. tuberculosis-specific T cells in humans,
suggesting that T cell responses to mycolic acids and GMM may play a
significant role in the protective host response to this important pathogen.
Studies in the current proposal will assess whether mycolic acids or GMM are
among the immunodominant T cell antigens of M. tuberculosis in humans infected
with this bacterium, and will seek to clarify the molecular basis for the
presentation and recognition of these novel T cell antigens. A combination of
preparative and synthetic chemistry will be used to generate a range of
structural analogues of mycolic acids and GMM. These will be studied for their
ability to be recognized by CD1b-restricted T cells, and for their ability to
bind directly to CD1b proteins. In addition, the structural basis for the
binding of these antigens to the CD1b protein will be analyzed by carrying out
site directed mutagenesis of residues forming the predicted ligand binding
groove of CD1b. These studies will lead to a detailed understanding of the
fundamental rules governing the interaction of a newly recognized class of T
cell antigens with their antigen presenting molecule. The identification and
detailed analysis of this newly recognized pathway for T cell antigen
recognition is likely to be important for understanding the human immune
response to M. tuberculosis and related pathogens, and has potential
implications for future vaccine development efforts.
Effective start/end date7/1/997/31/21


  • Medicine(all)
  • Immunology and Microbiology(all)
  • Cell Biology
  • Microbiology
  • Immunology


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