The major histocompatibility complex (MHC) molecules are responsible for the presentation of antigens to T cells. Two structurally similar types of molecules, class I and class II, have evolved binding grooves that can accommodate a variety of peptidic antigens. While a given MHC molecule may only be able to bind a subfraction of the universe of antigenic peptides, the existence of multiple iso- and allelic forms of the class I and II molecules ascertain that the species has the capacity of present most antigens. However similar class I and class II molecules are with regard to peptide binding, they present peptides of different origins in vivo. Thus, class I molecules primarily associate with peptides derived from proteins manufactured by the class I-expressing cell while the class II molecules usually obtain their peptides from exogenous proteins, which have been imported into the cell by endocytosis. The mechanisms responsible for this dichotomy are poorly understood but one contributing factor is the invariant chain (Ii). This molecule associates with class II chains in the endoplasmic reticulum (ER) and prevents peptide binding to class II molecules. After transport to a post-Golgi compartment, Ii is released and the class II molecules are able to acquire peptides. Thus, Ii may be the most important single factor responsible for the class II binding of exogenous peptides. To accomplish its task, Ii is endowed with structural motifs that targets various forms of the molecules to different subcellular compartments. The precise nature of these targeting signals will be determined. Subcellular fractionation analyses and morphological analyses will reveal which routes the various forms of Ii take in the cell to reach their destinations. These analyses will reveal where class II molecules obtain peptides. Such information will be invaluable in designing novel vaccines and should shed light on how self-molecules might give rise to auto-immune reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM046411-03
Application #
3305842
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1991-07-01
Project End
1994-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037