Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses

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.