| T cell priming to exogenous antigens reflects regulated antigen processing in dendritic cells, subsequent homing to lymph nodes, sustained interactions between T cells and antigen-bearing dendritic cells, and ultimately, selective T cell activation and differentiation. During antigen presentation, HLA-DM edits the peptide repertoire presented by MHC class II molecules by professional APC, favoring presentation of some peptides over others. An intrinsic property of the class II:peptide complex was identified to be the key determinant that dictates both the specificity of an emerging CD4 T cell response, and the efficiency of antigen presentation by DM-positive APC. Immunodominant peptides possess extremely long half-lives with class II molecules (t 1/2>150 h), while cryptic peptides displayed half lives of less than 10 h. The intrinsic kinetic stability of class II:peptide complexes is also tightly correlated with the effects of DM editing within APC. Modulating the kinetic stability of four independent peptides correspondingly altered the immunogenicity in vivo, as well as the magnitude and direction of DM editing within APC expressing DM. Collectively, these results suggest that for a given peptide, the pattern of DM editing in APC can be rationally modulated, leading to the desired presentation on the surface of APC, and thereby ensuring recruitment of the preferred CD4 T cells during an immune response to antigen. |
