Interactions between the T-cell receptor (TCR) and self-peptide–MHC (spMHC) have been hypothesized to modulate T-cell reactivity in the periphery. Recent studies examining CD4 + T-cell responses to spMHC class II describe apparently contradictory findings and arrive at opposite conclusions. One explanation for these seemingly disparate results could be the use of mice that were assumed to be MHC class II null but might express some uncommon MHC class II heterodimers.