DM determines the cryptic and immunodominant fate of T cell epitopes

The ability of the immune system to focus T cell responses against a select number of potential epitopes of a complex antigen is termed immunodominanc e. Epitopes that trigger potent T cell activation, after in vivo priming, a re classified as immunodominant. By contrast, determinants that fail to eli cit any response are called cryptic. DM, a major histocompatibility complex (MHC) heterodimer, plays a pivotal role in the presentation of MHC class I I-restricted epitopes by catalyzing the exchange of class II-associated inv ariant chain peptide with the antigen-derived peptides within the MHC class II binding groove. Using L cells transfected with genes for MHC class II, invariant chain, and DM, we have studied the contribution of DM in the pres entation of two cryptic (peptide 11-25 and peptide 20-35) and one dominant (peptide 106-116) epitope of hen egg white lysozyme (HEL). Cells lacking DM heterodimers efficiently display the determinants HEL 11-25 and HEL 20-35 to T cells. Strikingly, however, cells expressing DM are severely compromis ed in their ability to present the cryptic HEL 11-25/A(d) and 20-35/A(d) ep itopes. DM-mediated antagonism of HEL 11-25/A(d) and 20-35/A(d) presentatio n could thus be central to 11-25/A(d) and 20-35/A(d) being cryptic epitopes in the HEL system. Interestingly, the display of the immunodominant epitop e of HEL, 106-116/E-d, and of a dominant epitope of sperm whale myoglobin ( SWM), 102-118/A(d), is entirely dependent on the expression of DM. Thus, ce lls lacking DM molecules are unable to efficiently express HEL 106-116/E-d and SWM 102-118/A(d) determinants. We conclude that the DM heterodimers dir ect the immunodominant and cryptic fate of antigenic epitopes in vivo.