The magnitude of CD4+ T cell recall responses is controlled by the duration of the secondary stimulus.

The parameters controlling the generation of robust CD4(+) T cell recall responses remain poorly defined. In this study, we compare recall responses by CD4(+) and CD8(+) memory T cells following rechallenge. Homologous rechallenge of mice immune to either lymphocytic choriomeningitis virus or Listeria monocytogenes results in robust CD8(+) T cell recall responses but poor boosting of CD4(+) T cell recall responses in the same host. In contrast, heterologous rechallenge with a pathogen sharing only a CD4(+) T cell epitope results in robust boosting of CD4(+) T cell recall responses. The disparity in CD4(+) and CD8(+) T cell recall responses cannot be attributed to competition for growth factors or APCs, as robust CD4(+) and CD8(+) T cell recall responses can be simultaneously induced following rechallenge with peptide-pulsed dendritic cells. Instead, CD4(+) T cell recall responses are dependent on the duration of the secondary challenge. Increasing the rechallenge dose results in more potent boosting of CD4(+) T cell recall responses and artificially limiting the duration of secondary infection following heterologous rechallenge adversely impacts the magnitude of CD4(+) T cell, but not CD8(+) T cell, recall responses. These findings suggest that rapid pathogen clearance by secondary CTL following homologous rechallenge prevents optimal boosting of CD4(+) T cell responses and therefore have important practical implications in the design of vaccination and boosting strategies aimed at promoting CD4(+) T cell-mediated protection.