In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

The independent influences of invariant chain (Ii) and HLA-DM molecules on the array of naturally processed peptides displayed by HLA-DR molecules were studied using transfected cell lines. The absence of Ii led to an altered set of HLA-DR-bound peptides as judged by the discriminating responses of alloreactive T cell clones. While most T cell clones raised against DR(+)Ii(+)DM(+) peripheral blood mononuclear cells (PBMC) failed to respond to DR(+)Ii(−)DM(−) cells, T cell clones raised against DR(+)Ii(−)DM(−) transfectants were not stimulated by DR(+)Ii(+)DM(+) cells. Furthermore, coexpression of HLA-DM with HLA-DR1 in the absence of Ii augmented responses of anti-PBMC T cell clones but inhibited allorecognition by T cell clones raised against DR(+)Ii(−)DM(−) transfectants. The conformational integrity of the class II molecules, as judged by serology, suggests that the patterns of reactivity of the T cell clones reflect specificity for different alloantigen-bound peptides. Hence, discordant regulation of expression of major histocompatibility complex class II, Ii, and HLA-DM molecules in vivo may lead to the display of novel self-peptides and possible interruption of self-tolerance.