STRUCTURAL BASIS OF IMMUNE FUNCTION IN THE MHC

Project: Research project

Project Details

Description

The long-term goal of the proposed study is to determine the nature and
functional significance of structural diversity among class l antigen
presenting molecules. Structural diversity in the class I peptide binding
site is known to influence the way individuals respond to specific
antigens by determining which antigens can be presented and by shaping the
adult T cell receptor repertoire. How this is accomplished at the
molecular level, however, is still being described. The studies proposed
here focus on the laboratory mouse because the class I molecules of this
species closely resemble the profiles of diversity and immunologic
function of class I molecules in humans, and as a laboratory animal, the
mouse is amenable to experimental manipulation. Recent studies illustrate
the importance of amino acid diversity among class I molecules to their
peptide binding and presentation properties. The hypothesis that amino
acid diversity in the class I peptide binding can be generally attributed
to effects on peptide binding will be examined by investigating three
apparent exceptions to this rule. T cell receptors are believed to make
contact with the o: helical region of class I molecules and form an
interface with the exposed portions of peptides bound for presentation.
How this results in the observed specificity at the molecular level will
be addressed by examining the molecular basis of recognition of two
structurally distinct class I molecules by the same T cell receptor.
Diversity within the antigen binding site influences the development of
the adult T cell repertoire. Several lines of recent evidence indicate
that this occurs as a consequence of differences in peptide binding during
both positive and negative selection. While the importance of peptide
presentation in negative selection is generally understood, no examples of
self peptides that function in positive selection have been described. A
scheme using T cell receptor transgenic mice is presented for identifying
a self peptide believed to function in positive selection. Furthermore,
genetic variants of a class I molecule known to be important in the
positive selection of several different T cell receptors will be used in
a bone marrow transplant model to analyze the relationship between
positive selection, peptides bound, and the antigens the selected T cell
receptors are capable of responding against as part of the adult T cell
repertoire.
StatusFinished
Effective start/end date4/1/906/30/00

ASJC

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