Computational prediction of HLA class II–restricted epitopes by CD4+ T cells is of great interest for understanding immune responses in the context of transplantation, autoimmunity, infection, and cancer, but it is a difficult and complex undertaking because of the open conformation of the HLA class II peptide binding groove that can accommodate peptides of variable length (10–30 aa long) and because of the fact that Ag processing and peptide loading are incompletely understood (85). The gene discussed is CD4; the disease is Autoimmunity.