NOVEL MUTANTS DEFINE GENES REQUIRED FOR THE EXPRESSION OF HUMAN HISTOCOMPATIBILITY LEUKOCYTE ANTIGEN DM - EVIDENCE FOR LOCI ON HUMAN-CHROMOSOME 6P

We and others have shown that the products of the HLA-DM locus are req uired for the intracellular assembly of major histocompatibility compl ex class II molecules with cognate peptides for antigen presentation. HLA-DM heterodimers mediate the dissociation of invariant chain (Ii)-d erived class II-associated Ii peptides (CLIP) from class II molecules and facilitate the loading of class II molecules with antigenic peptid es. Here we describe novel APC mutants with defects in the formation o f class II-peptide complexes. These mutants express class II molecules which are conformationally altered, and an aberrantly high percentage oi these class II molecules are associated with Ii-derived CLIP. This phenotype resembles that of DM null mutants. However, we show that th e defects in two of these new mutants do not map to the DM locus. Neve rtheless, our evidence suggests that the antigen processing defective phenotype in these mutants results from deficient DM expression. These mutants thus appear to define genes in which mutations have different ial effects on the expression of conventional class II molecules and D M molecules. Our data are most consistent with these factors mapping t o human chromosome 6p. Previous data have suggested that the expressio n of DM and class II genes are coordinately regulated. The results rep orted here suggest that DM and class II can also be differentially reg ulated, and that this differential regulation has significant effects on class II-restricted antigen processing.