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 immunodominance. Epitopes that trigger potent T cell activation, after in vivo priming, are classified as immunodominant. By contrast, determinants that fail to elicit any response are called cryptic. DM, a major histocompatibility complex (MHC) heterodimer, plays a pivotal role in the presentation of MHC class II–restricted epitopes by catalyzing the exchange of class II–associated invariant 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 presentation 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 compromised in their ability to present the cryptic HEL 11–25/A^d and 20–35/A^d epitopes. DM-mediated antagonism of HEL 11–25/A^d and 20–35/A^d presentation 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 epitope 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, cells 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 direct the immunodominant and cryptic fate of antigenic epitopes in vivo.