CD4⁺ T cell help is important for the generation of CD8⁺ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4⁺ T cells for memory CD8⁺ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8⁺ T cell responses markedly enlarged the population size of antigen-specific CD8⁺ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8⁺ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8⁺ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4⁺CD25⁺ T cells. Our results demonstrate that CD4⁺ T cells control the CD8⁺ T cell response in two directions. Initially, they promote the generation of a CD8⁺ T cell responses and later they restrain the strength of the CD8⁺ T cell memory response. Down-modulation of CD8⁺ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.