INVARIANT CHAIN PREVENTS THE HLA-DR-RESTRICTED PRESENTATION OF A CYTOSOLIC PEPTIDE

Three properties of the HLA-DR-associated invariant chain (li) may con tribute to the distinction between the class I and class II Ag present ation pathways. First, li prevents peptide binding to alpha beta li co mplexes. Second, li promotes assembly of class II alpha beta heterodim ers and their transport out of the endoplasmic reticulum. Third, li pr ovides a targeting signal for the transport of class II molecules to e ndocytic compartments. However, it is not known whether li can prevent class li-restricted T cell recognition of endogenous peptides transpo rted into the endoplasmic reticulum. In addition, recent evidence has indicated that, in the absence of li, newly synthesized class II molec ules cannot form stable complexes with peptides. In this study, transf ected human fibroblast cells expressing HLA-DR1 alone or with an exces s of li were tested for their ability to present a DR1-restricted epit ope of the influenza virus matrix protein produced as a short cytosoli c peptide by use of an episomal expression vector. Presentation to a D R1-restricted T cell clone was very efficient in cells expressing clas s II molecules without li, but not in cells expressing class II with l i. The inhibition by li was specific for the endogenous cytosolic pept ide, because the same epitope processed from exogenous influenza virus particles was presented only by cells expressing class II with li. li did not inhibit the HLA-A2-restricted presentation of another cytosol ic peptide. Thus, T cells can detect a cytosolic peptide loaded onto c lass II alpha beta heterodimers, and li prevents such endogenous pepti de presentation.