Here we report a unique role for MHC II-peptide complexes in controlling immune responses of naïve CD8 T cells. Compared with CD8 T cells from WT mice, CD8 T cells isolated from MHC II(-/-) mice hyperproliferated under lymphopenic conditions, differentiated into effector cells producing proinflammatory cytokines, and mediated more severe tissue inflammation. The elevated responses of MHC II(-/-) CD8 T cells were due to the absence of MHC II, but not CD4, T cells. The hyperreactivity appeared to be a feature of mature T cells, given its absence in CD8 single positive thymocytes derived from MHC II(-/-) mice. Expression of the MHC II ligand LAG3 was markedly enhanced during in vivo activation of MHC II(-/-) CD8 T cells, and blockade of MHC II-LAG3 interactions further enhanced T-cell expansion. Importantly, CD8 T cells isolated from H-2M(-/-) mice expressing WT levels of MHC II also displayed hyperresponsiveness similar to that of MHC II(-/-) CD8 T cells, suggesting that peptides presented on MHC II are involved in the control of CD8 T-cell responses. Our results uncover a previously undefined MHC II-dependent regulation that tunes CD8 T-cell reactivity and may have implications for an improved understanding of CD8 T-cell homeostasis and functions.